Thio-substituted tricyclic and bicyclic aromatic methanesulfinyl derivatives

ABSTRACT

The present invention is related to chemical compositions, processes for the preparation thereof and uses of the composition. Particularly, the present invention relates to compositions of compounds of Formula (A): 
                         
wherein Ar, Y, R 1  and q are as defined herein; and their use in the treatment of diseases, including treatment of sleepiness, promotion of wakefulness, treatment of Parkinson&#39;s disease, cerebral ischemia, stroke, sleep apneas, eating disorders, stimulation of appetite and weight gain, treatment of attention deficit hyperactivity disorder (“ADHD”), enhancing function in disorders associated with hypofunctionality of the cerebral cortex, including, but not limited to, depression, schizophrenia, fatigue, in particular, fatigue associated with neurologic disease, such as multiple sclerosis, chronic fatigue syndrome, and improvement of cognitive dysfunction.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Application Ser. No.11/103,951, filed Apr. 12, 2005, now U.S. Pat. No. 7,119,214, which inturn claims priority of U.S. Provisional Application Ser. No.60/569,330, filed May 7, 2004 and European Patent Application No.04290980.4, filed Apr. 13, 2004. The complete disclosures of these priorapplications are incorporated herein by reference in their entiretiesfor all purposes.

FIELD OF THE INVENTION

The present invention is related to chemical compositions, processes forthe preparation thereof and uses of the composition. Particularly, thepresent invention relates to compositions of compounds of Formula (A):

and their use in the treatment of diseases, including treatment ofsleepiness, promotion and/or improvement of wakefulness, preferablyimprovement of wakefulness in patients with excessive sleepinessassociated with narcolepsy, sleep apnea, preferably obstructive sleepapnea/hypopnea, and shift work disorder; treatment of Parkinson'sdisease; Alzheimer's disease; cerebral ischemia; stroke; eatingdisorders; attention deficit disorder (“ADD”), attention deficithyperactivity disorder (“ADHD”); depression; schizophrenia; fatigue,preferably fatigue associated with cancer or neurological diseases, suchas multiple sclerosis and chronic fatigue syndrome; stimulation ofappetite and weight gain and improvement of cognitive dysfunction.

BACKGROUND OF THE INVENTION

The compounds disclosed herein are related to the biological andchemical analogs of modafinil. Modafinil, C₁₅H₁₅NO₂S, also known as2-(benzhydrylsulfinyl)acetamide, or2-[(diphenylmethyl)sulfinyl]acetamide, a synthetic acetamide derivativewith wake-promoting activity, has been described in French Patent No. 7805 510 and in U.S. Pat. No. 4,177,290 (“the '290 patent”). It has beenapproved by the United States Food and Drug Administration for use inthe treatment of excessive daytime sleepiness associated withnarcolepsy. Methods for preparing modafinil and several derivatives aredescribed in the '290 patent. The levorotatory isomer of modafinil,along with additional modafinil derivatives are described in U.S. Pat.No. 4,927,855, and are reported to be useful for treatment ofhypersomnia, depression, Alzheimer's disease and to have activitytowards the symptoms of dementia and loss of memory, especially in theelderly.

Modafinil has also been described as a useful agent in the treatment ofParkinson's disease (U.S. Pat. No. 5,180,745); in the protection ofcerebral tissue from ischemia (U.S. Pat. No. 5,391,576); in thetreatment of urinary and fecal incontinence (U.S. Pat. No. 5,401,776);and in the treatment of sleep apneas and disorders of central origin(U.S. Pat. No. 5,612,379). In addition, modafinil may be used in thetreatment of eating disorders, or to promote weight gain or stimulateappetite in humans or animals (U.S. Pat. No. 6,455,588), or in thetreatment of attention deficit hyperactivity disorder (U.S. Pat. No.6,346,548), or fatigue, especially fatigue associated with multiplesclerosis (U.S. Pat. No. 6,488,164). U.S. Pat. No. 4,066,686 describesvarious benzhydrylsulphinyl derivatives as being useful in therapy fortreating disturbances of the central nervous system.

Several published patent applications describe derivative forms ofmodafinil and the use of modafinil derivatives in the treatment ofvarious disorders. For example, PCT publication WO 99/25329 describesvarious substituted phenyl analogs of modafinil as being useful fortreating drug-induced sleepiness, especially sleepiness associated withadministration of morphine to cancer patients. U.S. Pat. No. 5,719,168and PCT Publication No. 95/01171 describes modafinil derivatives thatare useful for modifying feeding behavior. PCT Publication No. 02/10125describes several modafinil derivatives of modafinil, along with variouspolymorphic forms of modafinil.

Additional publications describing modafinil derivatives include U.S.Pat. No. 6,492,396, and PCT Publication No. WO 02/10125.

Terauchi, H, et al. described nicotinamide derivatives useful as ATP-aseinhibitors (Terauchi, H, et al, J. Med. Chem., 1997, 40, 313-321). Inparticular, several N-alkyl substituted 2-(Benzhydrylsulfinyl)nicotinamides are described.

U.S. Pat. Nos. 4,980,372 and 4,935,240 describebenzoylaminophenoxybutanoic acid derivatives. In particular, sulfidederivatives of modafinil containing a phenyl and substituted phenyllinker between the sulfide and carbonyl, and a substituted aryl in theterminal amide position, are disclosed.

Other modafinil derivatives have been disclosed wherein the terminalphenyl groups are constrained by a linking group. For example, in U.S.Pat. No. 5,563,169, certain xanthenyl and thiaxanthenyl derivativeshaving a substituted aryl in the terminal amide position are reported.

Other xanthenyl and thiaxanthenyl derivatives are disclosed in Annis, I;Barany, G. Pept. Proc. Am. Pept. Symp. 15^(th) (Meeting Date 1997)343-344, 1999 (preparation of a xanthenyl derivative of Ellman'sReagent, useful as a reagent in peptide synthesis); Han, Y.; Barany, G.J. Org. Chem., 1997, 62, 3841-3848 (preparation of S-xanthenyl protectedcysteine derivatives, useful as a reagent in peptide synthesis); andEl-Sakka, I. A., et al. Arch. Pharm. (Weinheim), 1994, 327, 133-135(thiaxanthenol derivatives of thioglycolic acid).

Thus, there is a need for novel classes of compounds that possess thebeneficial properties. It has been discovered that a class of compounds,referred to herein as substituted thioacetamides, are useful as agentsfor treating or preventing various diseases or disorders disclosedherein.

SUMMARY OF THE INVENTION

The present invention in one aspect is directed to various novelcompounds of structure:

and its stereoisomeric forms, mixtures of stereoisomeric forms, orpharmaceutically acceptable salt forms thereof, wherein the constituentmembers are defined infra.

Another object of the present invention is to provide pharmaceuticalcompositions comprising the compounds of the present invention whereinthe compositions comprise one or more pharmaceutically acceptableexcipients and a therapeutically effective amount of at least one of thecompounds of the present invention, or a pharmaceutically acceptablesalt or ester form thereof.

Another object of the present invention is to provide methods oftreating or preventing diseases or disorders, including treatment ofsleepiness, promotion and/or improvement of wakefulness, preferablyimprovement of wakefulness in patients with excessive sleepinessassociated with narcolepsy, sleep apnea, preferably obstructive sleepapnea/hypopnea, and shift work disorder; treatment of Parkinson'sdisease; Alzheimer's disease; cerebral ischemia; stroke; eatingdisorders; attention deficit disorder (“ADD”), attention deficithyperactivity disorder (“ADHD”); depression; schizophrenia; fatigue,preferably fatigue associated with cancer or neurological diseases, suchas multiple sclerosis and chronic fatigue syndrome stimulation ofappetite and weight gain and improvement of cognitive dysfunction.

These and other objects, features and advantages of the substitutedbenzylthioalkyl will be disclosed in the following detailed descriptionof the patent disclosure.

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment, the present invention provides novel compounds offormula (A):

wherein

-   Ar is:

Wherein:

-   -   U is CH₂, CR²⁵R²⁶, O, S(O)_(y), NR¹⁰, C(═O), C(═S), CHOH,        CHOR¹⁴, C═NOR¹⁴, or C═NNR¹²R¹³;

V and W are independently selected from a bond, CH₂, CR²⁵R²⁶, O,S(O)_(y), NR¹⁰, C(═O), C(═S), CHOH, CHOR¹⁴, C═NOR¹⁴, or C═NNR¹²R¹³;

-   -   rings A, B, and C are optionally substituted with one to three        groups selected from F, Cl, Br, I, OR²², OR²⁷, NR²³R²⁴, NHOH,        NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇        cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6        membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,        C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴,        NR²¹C(═S)R²², and S(O)_(y)R²²;    -   ring D is optionally substituted with one group selected from        C₁-C₆ alkyl, phenyl, and 5-10 membered heteroaryl;

-   Y is C₁-C₆ alkylene; or    -   (C₁-C₄ alkylene)_(m)-Z-(C₁-C₄ alkylene)_(n);        -   wherein said alkylene groups are optionally substituted with            one to three R²⁰ groups;

-   Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10    membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered    heterocycloalkylene; wherein said arylene, heteroarylene,    cycloalkylene, and heterocycloalkylene groups are optionally    substituted with one to three R²⁰ groups;

-   R¹ is selected from H, NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹,    OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³,    NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, NR²¹S(O)₂R¹²R¹³, and C(═O)NR¹¹OR²²;

-   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl,    C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl and aryl    groups are optionally substituted with one to three R²⁰ groups;

-   R¹¹ at each occurrence is independently selected from H, C₁-C₆    alkyl, and C₆-C₁₀ aryl; wherein said alkyl and aryl groups are    optionally substituted with one to three R²⁰ groups;

-   R¹² and R¹³ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, C₆-C₁₀ aryl, and NR²³R²⁴, or R¹² and R¹³, together    with the nitrogen to which they are attached, form a 3-7 membered    heterocyclic ring;    -   wherein said alkyl and aryl groups and heterocyclic ring are        optionally substituted with one to three R²⁰ groups;

-   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,    C₆-C₁₀ aryl, and alkylaryl;    -   wherein said alkyl, aryl and alkylaryl groups are optionally        substituted with one to three R²⁰ groups;

-   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,    OR²², OR²⁷, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl optionally    substituted with OH, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,    3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,    arylalkyl, ═O, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,    NR²¹C(═O)R²², NR²¹CO₂R²², NR²²CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²²,    and S(O)_(y)R²²;

-   R²¹ at each occurrence is independently selected from H and C₁-C₆    alkyl;

-   R²² at each occurrence is independently selected from H, C₁-C₆ alkyl    optionally substituted with OH, arylalkyl and C₆-C₁₀ aryl;

-   R²³ and R²⁴ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the    nitrogen to which they are attached, form a 3-7 membered    heterocyclic ring optionally substituted with ═O;

-   R²⁵ and R²⁶ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²⁵ and R²⁶, together with the    carbon to which they are attached, form a 3-7 membered heterocyclic    ring;

-   R²⁷ at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;

-   m is 0 or 1;

-   n is 0 or 1;

-   q is 0, 1, or 2;

-   y is 0, 1, or 2;    with the exclusion of the compounds wherein:    -   U is CH₂, C(═O), CH(CH₃), S or C═NNHPh; and    -   Y is CH₂; and    -   R¹ is H;        and with the exclusion of the compounds wherein:    -   U is CH₂; and    -   Y is C₁-C₆ alkylene optionally substituted with C₁-C₆ alkylene;        and    -   R¹ is CONH₂, or CO₂R¹¹ with R¹¹═H or C₁-C₆ alkyl;        and with the exclusion of the compounds:

-   3-[(methylthio)methyl]-2-phenyl-1H-inden-1-one

-   3-[(methylsulfinyl)methyl]-2-phenyl-1H-inden-1-one    and the stereoisomeric forms, mixtures of stereoisomeric forms or    pharmaceutically acceptable salts forms thereof.

Preferably, when V is a bond, and W is O, S(O)_(y), or NR¹⁰, ring D issubstituted by a phenyl group.

In a second embodiment, the present invention provides novel compoundsof formula (I):

wherein

-   Ar is

-   -   U is CH₂, CR²⁵R²⁶, O, S(O)_(y), NR¹⁰, C(═O), C(═S), CHOH,        CHOR¹⁴, C═NOR¹⁴, or C═NNR¹²R¹³;    -   V and W are independently selected from a bond, CH₂, CR²⁵R²⁶, O,        S(O)_(y), NR¹⁰, C(═O), C(═S), CHOH, CHOR¹⁴, C═NOR¹⁴, or        C═NNR¹²R¹³;    -   rings A, B, and C are optionally substituted with one to three        groups selected from F, Cl, Br, I, OR²², OR²⁷, NR²³R²⁴, NHOH,        NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇        cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6        membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,        C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴,        NR²¹C(═S)R²², and S(O)_(y)R²²;    -   ring D is optionally substituted with one group selected from        C₁-C₆ alkyl, phenyl, and 5-10 membered heteroaryl;

-   Y is C₁-C₆ alkylene;    -   (C₁-C₄ alkylene)_(m)-Z¹-(C₁-C₄ alkylene)_(n);    -   C₁-C₄ alkylene-Z²-C₁-C₄ alkylene;        -   wherein said alkylene groups are optionally substituted with            one to three R²⁰ groups;

-   Z¹ is CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10 membered heteroarylene,    -   C₃-C₆ cycloalkylene, or 3-6 membered heterocycloalkylene;        wherein said arylene, heteroarylene, cycloalkylene, and        heterocycloalkylene groups are optionally substituted with one        to three R²⁰ groups;

-   Z² is O, NR^(10A), or S(O)_(y);

-   R¹ is selected from H, NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹,    OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³,    NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, NR²¹S(O)₂NR¹²R¹³, and C(═O)NR¹¹OR²²;

-   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl,    C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl and aryl    groups are optionally substituted with one to three R²⁰ groups;

-   R¹¹ at each occurrence is independently selected from H, C₁-C₆    alkyl, and C₆-C₁₀ aryl; wherein said alkyl and aryl groups are    optionally substituted with one to three R²⁰ groups;

-   R¹² and R¹³ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, C₆-C₁₀ aryl, and NR²³R²⁴, or R¹² and R¹³, together    with the nitrogen to which they are attached, form a 3-7 membered    heterocyclic ring;    -   wherein said alkyl and aryl groups and heterocyclic ring are        optionally substituted with one to three R²⁰ groups;

-   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,    C₆-C₁₀ aryl, and alkylaryl; wherein said alkyl, aryl and alkylaryl    groups are optionally substituted with one to three R²⁰ groups;

-   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,    OR²², OR²⁷, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl optionally    substituted with OH, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,    3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,    arylalkyl, ═O, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,    NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and    S(O)_(y)R²²;

-   R²¹ at each occurrence is independently selected from H and C₁-C₆    alkyl;

-   R²² at each occurrence is independently selected from H, C₁-C₆ alkyl    optionally substituted with OH, arylalkyl and C₆-C₁₀ aryl;

-   R²³ and R²⁴ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the    nitrogen to which they are attached, form a 3-7 membered    heterocyclic ring optionally substituted with ═O;

-   R²⁵ and R²⁶ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²⁵ and R²⁶, together with the    carbone to which they are attached, form a 3-7 membered heterocyclic    ring;

-   R²⁷ at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;

-   m is 0 or 1;

-   n is 0 or 1;

-   q is 0, 1, or 2;

-   y is 0, 1, or 2;    and the stereoisomeric forms, mixtures of stereoisomeric forms or    pharmaceutically acceptable salts forms thereof.

Preferably, when V is a bond, and W is O, S(O)_(y), or NR¹⁰, ring D issubstituted by a phenyl group.

In another embodiment, the present invention includes a compound offormula (II):

wherein

-   Ar is:

-   -   U is CH₂, O, S(O)_(y), or NR¹⁰;    -   V and W are independently selected from a bond, O, S(O)_(y), or        NR¹⁰;    -   rings A, B, and C are optionally substituted with one to three        groups selected from F, Cl, Br, I, OR²², OR²⁷, NR²³R²⁴, NHOH,        NO₂, CN, CF₃, C₁-C₆ alkyl, phenyl, arylalkyl, and C(═O)R²²;    -   ring D is optionally substituted with one group selected from        C₁-C₆ alkyl, and phenyl;

-   Y is C₁-C₆ alkylene;    -   C₁-C₄ alkylene-Z¹-(C₁-C₄ alkylene)_(n);    -   C₁-C₄ alkylene-Z²-C₁-C₄ alkylene;        -   wherein said alkylene groups are optionally substituted with            one to three R²⁰ groups;

-   Z¹ is CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10 membered heteroarylene,    -   C₃-C₆ cycloalkylene, or 3-6 membered heterocycloalkylene;        wherein said arylene, heteroarylene, cycloalkylene, and        heterocycloalkylene groups are optionally substituted with one        to three R²⁰ groups;

-   Z² is O, NR^(10A), or S(O)_(y);

-   R¹ is selected from NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹,    C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹,    NR²¹C(═O)NR¹²R¹³, NR²¹S(O)₂NR¹²R¹³, and C(═O)NR¹¹OR²¹;

-   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl,    C(═O)R¹⁴, and S(O)_(y)R¹⁴;    -   wherein said alkyl and aryl groups are optionally substituted        with one to three R²⁰ groups;

-   R¹¹ at each occurrence is independently selected from H, and C₁-C₆    alkyl; wherein said alkyl and aryl groups are optionally substituted    with one to three R²⁰ groups;

-   R¹² and R¹³ at each occurrence are each independently selected from    H, and C₁-C₆ alkyl, and NR²³R²⁴, or R¹² and R¹³, together with the    nitrogen to which they are attached, form a 3-7 membered    heterocyclic ring;    -   wherein said alkyl and aryl groups and heterocyclic ring are        optionally substituted with one to three R²⁰ groups;

-   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl    and C₆-C₁₀ aryl; wherein said alkyl, aryl and alkylaryl groups are    optionally substituted with one to three R²⁰ groups;

-   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,    OR²², OR²⁷, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl optionally    substituted with OH, phenyl, ═O, C(═O)R²², CO₂R²², OC(═O)R²²,    C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴,    NR²¹OC(═S)R²², and S(O)_(y)R²²;

-   R²¹ at each occurrence is independently selected from H and C₁-C₆    alkyl;

-   R²² at each occurrence is independently selected from H, C₁-C₆ alkyl    optionally substituted with OH, phenyl, and benzyl;

-   R²³ and R²⁴ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the    nitrogen to which they are attached, form a 3-7 membered    heterocyclic ring optionally substituted with ═O;

-   R²⁵ and R²⁶ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and phenyl, or R²⁵ and R²⁶, together with the carbon    to which they are attached, form a 3-7 membered heterocyclic ring;

-   R²⁷ at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;

-   n is 0 or 1;

-   q is 0, 1, or 2;

-   y is 0, 1, or 2;    and the stereoisomeric forms, mixtures of stereoisomeric forms or    pharmaceutically acceptable salts forms thereof.

An additional aspect of the present invention includes compounds offormula (A) and formulas (I) and (II) wherein Y is C₁-C₆ alkylene, C₁-C₄alkylene-Z¹-C₁-C₄ alkylene, or C₁-C₄ alkylene-Z²-C₁-C₄ alkylene, whereinsaid alkylene groups are optionally substituted with one to three C₁-C₆alkyl groups; Z¹ is CR²¹═CR²¹, C≡C, or phenyl; Z² is O, NR^(10A), orS(O)_(y); R¹ is selected from NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹,and C(═O)NR¹²R¹³. In other aspects, Y is C₁-C₆ alkylene, or C₁-C₄alkylene-Z¹-C₁-C₄ alkylene. In additional aspects, Y is C₁-C₆ alkylene.In further aspects, R¹ is C(═O)NR¹²R¹³.

In certain aspects of the present invention, there are includedcompounds of formula (A) and formulas (I) and (II) wherein Ar isdibenzofuranyl. Other aspects include compounds where Ar isdibenzothienyl. Other aspects include compounds where Ar is fluorenyl.Other aspects include compounds where Ar is phenylbenzofuranyl. Otheraspects include compounds where Ar is phenylbenzothiophenyl. Otheraspects include compounds where Ar is phenylindolyl. Other aspectsinclude compounds where Ar is phenylbenzodioxinyl.

In additional aspects of the present invention, there are includedcompounds of formula (A) and formulas (I) and (II) wherein Ar has any ofthe values of the previous embodiments and q is 1.

Other aspects of the present invention include compounds of formula (A)and formulas (I) and (II) wherein Ar and q have any of the values of theprevious embodiments, and Y is C₁-C₆ alkylene, particularly those whereY is CH₂ or CH₂CH₂, and most particularly those where Y is CH₂.

Additional aspects of the present invention include compounds of formula(A) and formulas (I) and (II) wherein Ar and q have any of the values ofthe previous embodiments, and Y is (C₁-C₄ alkylene)_(m)-Z¹-(C₁-C₄alkylene)_(n) wherein Z¹ is CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 memberedheterocycloalkylene. Other aspects include those compounds where Y isC₁-C₄ alkylene-Z¹. Other aspects include those where Y is Z¹-C₁-C₄alkylene. Additional aspects include compounds where Y is C₁-C₄alkylene-Z¹-C₁-C₄ alkylene.

Further aspects of the present invention include compounds of formula(A) and formulas (I) and (II) wherein Ar, Y, and q have any of thevalues of the previous embodiments, and Z¹ is CR²¹═CR²¹, or C≡C. Otheraspects include compounds where Z¹ is C₆-C₁₀ arylene, or C₃-C₆cycloalkylene, particularly those where Z¹ is phenyl. Other aspectsinclude compounds where Z¹ is 5-10 membered heteroarylene, or 3-6membered heterocycloalkylene.

Further aspects of the present invention include compounds of formula(A) and formulas (I) and (II) wherein Ar and q have any of the values ofthe previous embodiments, and Y is (C₁-C₄ alkylene)_(m)-Z²-(C₁-C₄alkylene)_(n) wherein Z² is O, NR^(10A), or S(O)_(y). Other aspectsinclude those compounds where Y is C₁-C₄ alkylene-Z², wherein R¹ cannotbe H. Other aspects include those compounds where Y is C₁-C₄alkylene-Z²-C₁-C₄ alkylene. Additional aspects include any of the aboveembodiments of Y wherein Z² is O. Additional aspects include any of theabove embodiments of Y wherein Z² is NR^(10A).

Further aspects of the present invention include compounds of formula(A) and formulas (I) and (II) wherein Ar, Y, Z¹, and Z², and q have anyof the values of the previous embodiments, and R¹ can be any valueselected from the following 12 enumerated paragraphs:

-   -   1. H.    -   2. NR¹²R¹³.    -   3. NR²¹C(═O)R¹⁴.    -   4. C(═O)R¹⁴.    -   5. CO₂R¹¹.    -   6. OC(═O)R¹¹.    -   7. C(═O)NR¹²R¹³.    -   8. C(═NR¹¹)NR¹²R¹³.    -   9. OC(═O)NR¹²R¹³.    -   10. NR²¹S(O)₂R¹¹.    -   11. NR²¹C(═O)NR¹²R¹³.    -   12. NR²¹S(O)₂NR¹²R¹³.    -   13. C(═O)NR¹¹OR²².

Other additional aspects of the present invention include compounds offormula (A) and formulas (I) and (II) wherein Ar, Y, Z¹, and Z², and qhave any of the values of the previous embodiments, and R¹ can be acombination of the values selected from the previous 13 enumeratedparagraphs. The preceding 13 enumerated paragraphs may be combined tofurther define additional preferred embodiments of compounds of thepresent invention. For example, one such combination includes NR¹²,NR¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³,C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, andNR²¹S(O)₂NR¹²R¹³, C(═O)NR¹¹NR²³R²⁴, C(═O)NR¹¹OR²², and C(═O)NR¹¹OR²².

Another such combination includes NR¹²R¹³, wherein R¹² and R¹³ are eachindependently selected from H and C₁-C₆ alkyl; NR²¹C(═O)R¹⁴;C(═O)NR¹²R¹³; C(═NR¹¹)NR¹²R¹³, and NR²¹C(═O)NR¹²R¹³;

A third such combination includes C(═O)R⁴, CO₂R¹¹, OC(═O)R¹¹,C(═O)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, and NR²¹S(O)₂NR¹²R¹³.

A fourth such combination includes NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹,OC(═O)R¹¹, C(═O)NR¹²R¹³, and C(═O)NR¹¹OR²².

A fifth such combination includes NR²¹C(═O)R¹⁴, and C(═O)NR¹²R¹³.

In still further aspects of the present invention, there are includedcompounds of formulas (III) and (IV):

wherein U, V and W have any of the values of the previous embodiments.

Additional aspects of the present invention include compounds of formula(A) and formulas (I) through (IV) wherein Ar, Y, Z¹, Z², R¹, and q haveany of the values of the previous embodiments, and R¹² and R¹³ are eachindependently selected from H and C₁-C₆ alkyl.

Other aspects of the present invention include compounds of formula (A)and formulas (I) through (IV) wherein Ar, Y, Z¹, Z², R¹, and q have anyof the values of the previous embodiments, and R¹² and R¹³ together withthe nitrogen to which they are attached, form a 3-7 memberedheterocyclic ring, particularly those where the heterocyclic ring is aheterocycloalkyl group, and more particularly those where theheterocyclic group is pyrrolidine or piperidine. In certain aspects, theheterocyclic ring is substituted with one R²⁰. In other aspects, theheterocyclic ring is unsubstituted.

In a preferred embodiment, Ar is dibenzofuranyl (U═O), dibenzothiophenyl(U═S) or fluorenyl (U═CH₂ or CR²⁵R²⁶).

Preferably, the ring A or B of such Ar groups is substituted with Cl, For OR²² wherein R²² represents preferably a (C₁-C₆)alkyl group, such asa OCH₃ group.

In another preferred embodiment, Ar is benzofuranyl (W is a bond and Vis O), benzothiophenyl (W is a bond and V is S), indol (W is a bond andV is N), or benzodioxinyl (W═V═O).

Preferably, the ring D of such Ar groups is substituted with a phenyl orCl.

In accordance with a preferred embodiment, q is 0 or 1.

Preferably, Y is an unsubstituted (C₁-C₆)alkylene group, more preferablya CH₂ or CH₂CH₂ group and most preferably a CH₂ group.

In accordance with a preferred embodiment, R¹ is C(═O)NR¹²R¹³, whereinR¹² and R¹³ independently represents H, NR²³R²⁴, (C₂-C₆)alkyl, or form a3-7-membered heterocyclic ring together with the nitrogen atom to whichthey are attached.

In accordance with a preferred embodiment, R¹² and/or R¹³ represent aNR²³R²⁴ wherein R²³ and R²⁴ together with the nitrogen to which they areattached, form a 3-7-membered heterocyclic ring, notably a 5-6-memberedheterocyclic ring such as morpholine.

In accordance with another preferred embodiment, R¹² and/or R¹³represent a (C₁-C₆) alkyl group selected from methyl, ethyl, propyl,i-propyl, optionally substituted with one to three R²⁰ groups.

In that context, preferred substituents of R¹² and/or R¹³ representing a(C₁-C₆)alkyl group are OR²², NR²³R²⁴.

Examples of substituents OR²² are notably OH and O(C₁-C₆)alkyloptionally substituted by OH such as OCH₂CH₂OH.

Examples of substituents NR²³R²⁴ are those wherein R²³ and R²⁴ togetherwith the nitrogen to which they are attached, form a 3-7-memberedheterocyclic ring, notably a 5-6-membered heterocyclic ring such aspyrrolidine, piperazine or morpholine, the pyrrolidine being optionallysubstituted by ═O.

In accordance with another preferred embodiment, R¹² and/or R¹³ form a3-7-membered heterocyclic ring together with the nitrogen atom to whichthey are attached wherein the heterocyclic ring is preferably a5-6-membered heterocyclic ring such as pyrrolidinyl, piperazinyl,piperidinyl or morpholinyl.

Heterocyclic ring may be substituted or unsubstituted.

Preferred heterocyclic ring substituents are OR²², ═O, C(═O)R²², CO₂R²²,C(═O)NR²³R²⁴, (C₁-C₆)alkyl optionally substituted with one to three OH.

Examples of substituents OR²² are notably OH.

Examples of substituents C(═O)R²² are notably those wherein R²² is H ora (C₁-C₆)alkyl group, such as C(═O)H or C(═O)CH₃.

Examples of substituents CO₂R²² are notably those wherein R²² is(C₁-C₆)alkyl or arylalkyl such as CO₂tBu, CO₂Et and CO₂CH₂Ph.

Examples of C(═O)NR²³R²⁴ substituents are notably those wherein R²³ andR²⁴ independently represent H or (C₁-C₆)alkyl such as C(═O)NH₂,C(═O)N(CH₃)₂, C(═O)NH(iPr), or those wherein R²³ and R²⁴, together withthe nitrogen to which they are attached, form a 3-7-memberedheterocyclic ring, notably a 5-6-membered heterocyclic ring such aspyrrolidine.

Examples of (C₁-C₆) alkyl groups substituted with one to three R²⁰groups are notably methyl, ethyl, propyl, —CH₂CH₂CH₂OH.

In a preferred embodiment of the present invention there are providedcompounds of formula (A) and formula (I):

wherein Ar, q, Y—R¹ are defined in the table 1 below.

The positions on the Ar groups are numbered as follows:

TABLE 1 Ex. n^(o) Ring Ar q Y—R¹ 16 Dibenzofuran-2-yl 0 CH₂CONH₂ 36Dibenzofuran-2-yl 1 CH₂CONH₂ Dibenzofuran-2-yl 0 CH₂CON(CH₃)₂ 54Dibenzofuran-2-yl 1 CH₂CON(CH₃)₂ Dibenzofuran-2-yl 0CH₂CO—N-pyrrolidinyl 55 Dibenzofuran-2-yl 1 CH₂CO—N-pyrrolidinylDibenzofuran-2-yl 0 CH₂CONHCH(CH₃)₂ 56 Dibenzofuran-2-yl 1CH₂CONHCH(CH₃)₂ Dibenzofuran-2-yl 0CH₂CO-1-(4-tert-butoxycarbonyl)-piperazinyl 57 Dibenzofuran-2-yl 1CH₂CO-1-piperazinyl Dibenzofuran-2-yl 0 CH₂CO-1-(4-acetyl)-piperazinyl58 Dibenzofuran-2-yl 1 CH₂CO-1-(4-acetyl)-piperazinyl Dibenzofuran-2-yl0 CH₂CONHCH₂CH₂OH 59 Dibenzofuran-2-yl 1 CH₂CONHCH₂CH₂OHDibenzofuran-2-yl 0 CH₂CO-1-(4-hydroxy)piperidinyl 60 Dibenzofuran-2-yl1 CH₂CO-1-(4-hydroxy)piperidinyl Dibenzofuran-2-yl 0CH₂CONHCH₂CH₂OCH₂CH₂OH 61 Dibenzofuran-2-yl 1 CH₂CONHCH₂CH₂OCH₂CH₂OH 15Dibenzofuran-2-yl 0 CH₂CO-1-[4-(2-hydroxyethyl)-piperazinyl] 34Dibenzofuran-2-yl 1 CH₂CO-1-[4-(2-hydroxyethyl)-piperazinyl]Dibenzofuran-2-yl 0 CH₂CO-1-(4-formyl)-piperazinyl 62 Dibenzofuran-2-yl1 CH₂CO-1-(4-formyl)-piperazinyl 63 Dibenzofuran-2-yl 1CH₂CO-1-(4-tert-butoxycarbonyl)-piperazinyl 35 Dibenzofuran-2-yl 1CH₂CO-1-(4-ethoxycarbonyl)-piperazinyl 64 Dibenzofuran-2-yl 1CH₂CO-1-(4-methyl)-piperazinyl Dibenzofuran-2-yl 0CH₂CO-1-(4-ethyl)-piperazinyl 65 Dibenzofuran-2-yl 1CH₂CO-1-(4-ethyl)-piperazinyl Dibenzofuran-2-yl 0CH₂CO-1-(4-propyl)-piperazinyl 66 Dibenzofuran-2-yl 1CH₂CO-1-(4-propyl)-piperazinyl Dibenzofuran-2-yl 0 CH₂CON-morpholinyl 67Dibenzofuran-2-yl 1 CH₂CON-morpholinyl Dibenzofuran-2-yl 0CH₂CO—N-ethyl-N-(2-hydroxy-ethyl) 68 Dibenzofuran-2-yl 1CH₂CO—N-ethyl-N-(2-hydroxy-ethyl) Dibenzofuran-2-yl 0CH₂CONHN-morpholinyl 69 Dibenzofuran-2-yl 1 CH₂CONHN-morpholinylDibenzofuran-2-yl 0 CH₂CO-4-(2-oxo-piperazinyl) 70 Dibenzofuran-2-yl 1CH₂CO4-(2-oxo-piperazinyl) 71 Dibenzofuran-2-yl 1CH₂CO-1-(4-isopropylaminocarbonyl)- piperazinyl 72 Dibenzofuran-2-yl 1CH₂CO-1-(4-aminocarbonyl)-piperazinyl 73 Dibenzofuran-2-yl 1CH₂CO-1-(4-pyrrolidinylcarbonyl)-piperazinyl 74 Dibenzofuran-2-yl 1CH₂CO-1-(4-dimethylaminocarbonyl)- piperazinyl 75 Dibenzofuran-2-yl 1CH₂CO-1-(4-benzyloxycarbonyl)-piperazinyl Dibenzofuran-2-yl 0CH₂CH₂CONH₂ 76 Dibenzofuran-2-yl 1 CH₂CH₂CONH₂ Dibenzofuran-2-yl 0CH₂CH₂CO-1-piperazinyl-N-Boc 77 Dibenzofuran-2-yl 1CH₂CH₂CO-1-piperazinyl 78 Dibenzofuran-2-yl 1CH₂CH₂CO-1-(4-acetyl)-piperazinyl 79 Dibenzofuran-2-yl 1CH₂CON-[3-(2-oxo-pyrrolidin-1-yl)-propyl] Dibenzofuran-2-yl 0CH₂CON-(2-pyrrolidin-1-yl-ethyl) 80 Dibenzofuran-2-yl 1CH₂CON-(2-pyrrolidin-1-yl-ethyl) Dibenzofuran-2-yl 0CH₂CON-(2-piperidin-1-yl-ethyl) 81 Dibenzofuran-2-yl 1CH₂CON-(2-piperidin-1-yl-ethyl) Dibenzofuran-2-yl 0CH₂CON-(2-morpholin-4-yl-ethyl) 82 Dibenzofuran-2-yl 1CH₂CON-(2-morpholin-4-yl-ethyl Dibenzofuran-2-yl 0 H 83Dibenzofuran-2-yl 1 H 6-Chloro-dibenzofuran-2-yl 0CH₂CO-1-piperazinyl-N-Boc 84 6-Chloro-dibenzofuran-2-yl 1CH₂CO-1-piperazinyl 6-Chloro-dibenzofuran-2-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 85 6-Chloro-dibenzofuran-2-yl 1CH₂CO-1-(4-acetyl)-piperazinyl 22 8-Chloro-dibenzofuran-2-yl 0CH₂CO-1-piperazinyl-N-Boc 41 8-Chloro-dibenzofuran-2-yl 1CH₂CO-1-piperazinyl 8-Chloro-dibenzofuran-2-yl 0 CH₂CONH₂ 868-Chloro-dibenzofuran-2-yl 1 CH₂CONH₂ 23 8-Chloro-dibenzofuran-2-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 42 8-Chloro-dibenzofuran-2-yl 1CH₂CO-1-(4-acetyl)-piperazinyl 146 8-Chloro-dibenzofuran-2-yl 2CH₂CO-1-(4-acetyl)-piperazinyl 21 8-Chloro-dibenzofuran-2-yl 0CH₂CO-1-(4-hydroxyethyl)-piperazinyl 40 8-Chloro-dibenzofuran-2-yl 1CH₂CO-1-(4-hydroxyethyl)-piperazinyl 17 8-Methoxy-dibenzofuran-2-yl 0CH₂CONH₂ 37 8-Methoxy-dibenzofuran-2-yl 1 CH₂CONH₂8-Methoxy-dibenzofuran-2-yl 0 CH₂CO-1-piperazinyl-N-Boc 878-Methoxy-dibenzofuran-2-yl 1 CH₂CO-1-piperazinyl8-Methoxy-dibenzofuran-2-yl 0 CH₂CO-1-(4-acetyl)-piperazinyl 888-Methoxy-dibenzofuran-2-yl 1 CH₂CO-1-(4-acetyl)-piperazinyl 268-Fluoro-dibenzofuran-2-yl 0 CH₂CO-1-piperazinyl-N-Boc 458-Fluoro-dibenzofuran-2-yl 1 CH₂CO-1-piperazinyl8-Fluoro-dibenzofuran-2-yl 0 CH₂CO-1-(4-acetyl)-piperazinyl 898-Fluoro-dibenzofuran-2-yl 1 CH₂CO-1-(4-acetyl)-piperazinyl 198-Fluoro-dibenzofuran-2-yl 0 CH₂CONH₂ 38 8-Fluoro-dibenzofuran-2-yl 1CH₂CONH₂ 4-Chloro-dibenzofuran-2-yl 0 CH₂CONH₂ 904-Chloro-dibenzofuran-2-yl 1 CH₂CONH₂ 4-Fluoro-dibenzofuran-2-yl 0CH₂CONH₂ 91 4-Fluoro-dibenzofuran-2-yl 1 CH₂CONH₂4-Chloro-dibenzofuran-2-yl 0 CH₂CO-1-(4-acetyl)-piperazinyl 924-Chloro-dibenzofuran-2-yl 1 CH₂CO-1-(4-acetyl)-piperazinyl4-Fluoro-dibenzofuran-2-yl 0 CH₂CO-1-(4-acetyl)-piperazinyl 934-Fluoro-dibenzofuran-2-yl 1 CH₂CO-1-(4-acetyl)-piperazinyl4-Fluoro-8-chloro-dibenzofuran- 0 CH₂CONH₂ 2-yl 944-Fluoro-8-chloro-dibenzofuran- 1 CH₂CONH₂ 2-yl Dibenzofuran-4-yl 0CH₂CONHCH₂CH₂OH 95 Dibenzofuran-4-yl 1 CH₂CONHCH₂CH₂OH Dibenzofuran-4-yl0 CH₂CONH₂ 96 Dibenzofuran-4-yl 1 CH₂CONH₂ Dibenzofuran-4-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 97 Dibenzofuran-4-yl 1CH₂CO-1-(4-acetyl)-piperazinyl Dibenzofuran-4-yl 0CH₂CO-1-(4-hydroxy)piperidinyl 98 Dibenzofuran-4-yl 1CH₂CO-1-(4-hydroxy)piperidinyl Dibenzofuran-4-yl 0CH₂CO-1-piperazinyl-N-Boc 99 Dibenzofuran-4-yl 1 CH₂CO-1-piperazinylDibenzofuran-4-yl 0 CH₂CON-(2-pyrrolidin-1-yl-ethyl) 100Dibenzofuran-4-yl 1 CH₂CON-(2-pyrrolidin-1-yl-ethyl) Dibenzofuran-4-yl 0CH₂CON-[3-(2-oxo-pyrrolidin-1-yl)-propyl] 101 Dibenzofuran-4-yl 1CH₂CON-[3-(2-oxo-pyrrolidin-1-yl)-propyl] Dibenzofuran-4-yl 0CH₂CON-(2-piperidin-1-yl-ethyl) 102 Dibenzofuran-4-yl 1CH₂CON-(2-piperidin-1-yl-ethyl) Dibenzofuran-4-yl 0CH₂CON-(2-morpholin-4-yl-ethyl) 103 Dibenzofuran-4-yl 1CH₂CON-(2-morpholin-4-yl-ethyl) Dibenzofuran-4-yl 0CH₂CO-1-(4-hydroxyethyl)-piperazinyl 104 Dibenzofuran-4-yl 1CH₂CO-1-(4-hydroxyethyl)-piperazinyl Dibenzofuran-3-yl 0CH₂CO-1-piperazinyl-N-Boc 105 Dibenzofuran-3-yl 1 CH₂CO-1-piperazinylDibenzofuran-1-yl 0 CH₂CO-1-piperazinyl-N-Boc 106 Dibenzofuran-1-yl 1CH₂CO-1-piperazinyl Dibenzofuran-3-yl 0 CH₂CO-1-(4-acetyl)-piperazinyl107 Dibenzofuran-3-yl 1 CH₂CO-1-(4-acetyl)-piperazinyl 25Dibenzothiophen-2-yl 0 CH₂CO-1-piperazinyl-N-Boc 44 Dibenzothiophen-2-yl1 CH₂CO-1-piperazinyl Dibenzothiophen-2-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 108 Dibenzothiophen-2-yl 1CH₂CO-1-(4-acetyl)-piperazinyl Dibenzothiophen-2-yl 0CH₂CO-1-(4-ethoxycarbonyl)-piperazinyl 109 Dibenzothiophen-2-yl 1CH₂CO-1-(4-ethoxycarbonyl)-piperazinyl 18 Dibenzothiophen-2-yl 0CH₂CONH₂ 39 Dibenzothiophen-2-yl 1 CH₂CONH₂ Dibenzothiophen-4-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 110 Dibenzothiophen-4-yl 1CH₂CO-1-(4-acetyl)-piperazinyl Fluoren-1-yl 0 CH₂CONHCH₂CH₂OH 111Fluoren-1-yl 1 CH₂CONHCH₂CH₂OH Fluoren-1-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 112 Fluoren-1-yl 1CH₂CO-1-(4-acetyl)-piperazinyl Fluoren-1-yl 0CH₂CO-1-(4-hydroxy)piperidinyl 113 Fluoren-1-yl 1CH₂CO-1-(4-hydroxy)piperidinyl Fluoren-1-yl 0 CH₂CONH₂ 114 Fluoren-1-yl1 CH₂CONH₂ Fluoren-1-yl 0 CH₂CO-1-(4-hydroxyethyl)-piperazinyl 115Fluoren-1-yl 1 CH₂CO-1-(4-hydroxyethyl)-piperazinyl Fluoren-1-yl 0CH₂CO-1-piperazinyl-N-Boc 116 Fluoren-1-yl 1 CH₂CO-1-piperazinylFluoren-2-yl 0 CH₂CONH₂ 117 Fluoren-2-yl 1 CH₂CONH₂ Fluoren-2-yl 0CH₂CON(CH₃)₂ 118 Fluoren-2-yl 1 CH₂CON(CH₃)₂ Fluoren-2-yl 0CH₂CO—N-pyrrolidinyl 119 Fluoren-2-yl 1 CH₂CO—N-pyrrolidinylFluoren-2-yl 0 CH₂CONHCH(CH₃)₂ 120 Fluoren-2-yl 1 CH₂CONHCH(CH₃)₂Fluoren-2-yl 0 CH₂CONHCH₂CH₂OH 121 Fluoren-2-yl 1 CH₂CONHCH₂CH₂OHFluoren-2-yl 0 CH₂CO-1-(4-hydroxy)piperidinyl 122 Fluoren-2-yl 1CH₂CO-1-(4-hydroxy)piperidinyl Fluoren-2-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 123 Fluoren-2-yl 1CH₂CO-1-(4-acetyl)-piperazinyl Fluoren-4-yl 0 CH₂CONH₂ 124 Fluoren-4-yl1 CH₂CONH₂ Fluoren-4-yl 0 CH₂CON(CH₃)₂ 125 Fluoren-4-yl 1 CH₂CON(CH₃)₂Fluoren-4-yl 0 CH₂CONHCH(CH₃)₂ 126 Fluoren-4-yl 1 CH₂CONHCH(CH₃)₂Fluoren-4-yl 0 CH₂CONHCH₂CH₂OH 127 Fluoren-4-yl 1 CH₂CONHCH₂CH₂OHFluoren-4-yl 0 CH₂CO-1-(4-hydroxy)piperidinyl 128 Fluoren-4-yl 1CH₂CO-1-(4-hydroxy)piperidinyl Fluoren-4-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 129 Fluoren-4-yl 1CH₂CO-1-(4-acetyl)-piperazinyl Fluoren-4-yl 0 CH₂CO-1-piperazinyl-N-Boc130 Fluoren-4-yl 1 CH₂CO-1-piperazinyl 24 Fluoren-4-yl 0CH₂CO-1-(4-hydroxyethyl)-piperazinyl 43 Fluoren-4-yl 1CH₂CO-1-(4-hydroxyethyl)-piperazinyl Fluoren-4-yl 0CH₂CO-1-(4-formyl)-piperazinyl 131 Fluoren-4-yl 1CH₂CO-1-(4-formyl)-piperazinyl 2-Phenylbenzofuran-3-yl 0 CH₂CONH₂ 1322-Phenylbenzofuran-3-yl 1 CH₂CONH₂ 2-Phenylbenzofuran-3-yl 0CH₂CO—N-pyrrolidinyl 133 2-Phenylbenzofuran-3-yl 1 CH₂CO—N-pyrrolidinyl2-Phenylbenzofuran-3-yl 0 CH₂CH₂CONH₂ 134 2-Phenylbenzofuran-3-yl 1CH₂CH₂CONH₂ 2-Phenylbenzofuran-3-yl 0 CH₂CH₂CO—N-pyrrolidinyl 1352-Phenylbenzofuran-3-yl 1 CH₂CH₂CO—N-pyrrolidinyl 202-Phenylbenzofuran-3-yl 0 CH₂CON(CH₃)₂ 46 2-Phenylbenzofuran-3-yl 1CH₂CON(CH₃)₂ 2-Phenylbenzofuran-3-yl 0 CH₂CH₂CON(CH₃)₂ 1362-Phenylbenzofuran-3-yl 1 CH₂CH₂CON(CH₃)₂ 2-Phenylbenzofuran-3-yl 0CH₂CONHCH(CH₃)₂ 137 2-Phenylbenzofuran-3-yl 1 CH₂CONHCH(CH₃)₂2-Phenylbenzofuran-3-yl 0 CH₂CH₂CONHCH(CH₃)₂ 138 2-Phenylbenzofuran-3-yl1 CH₂CH₂CONHCH(CH₃)₂ 2-Phenylbenzofuran-3-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 139 2-Phenylbenzofuran-3-yl 1CH₂CO-1-(4-acetyl)-piperazinyl 2-Phenylbenzofuran-3-yl 0CH₂CH₂CO-1-(4-acetyl)-piperazinyl 140 2-Phenylbenzofuran-3-yl 1CH₂CH₂CO-1-(4-acetyl)-piperazinyl 3-Phenylbenzothiophen-2-yl 0 CH₂CONH₂141 3-Phenylbenzothiophen-2-yl 1 CH₂CONH₂ 27 3-phenylbenzothiophen-2-yl0 CH2—CO—N-pyrrolidinyl 28 3-phenylbenzothiophen-2-yl 0 CH2—CON(CH₃)₂ 293-phenylbenzothiophen-2-yl 0 CH2—CONHCH(CH₃)₂ 303-phenylbenzothiophen-2-yl 0 CH2—CO-1-(4-hydroxy)-piperidinyl 313-phenylbenzothiophen-2-yl 0 CH2—CO-1-(4-acetyl)-piperazinyl 323-phenylbenzothiophen-2-yl 0 CH2—CONH(CH₂)₂OH 473-phenylbenzothiophen-2-yl 1 CH2—CO—N-pyrrolidinyl 483-phenylbenzothiophen-2-yl 1 CH2—CON(CH₃)₂ 49 3-phenylbenzothiophen-2-yl1 CH2—CONHCH(CH₃)₂ 50 3-phenylbenzothiophen-2-yl 1CH2—CO-1-(4-hydroxy)-piperidinyl 51 3-phenylbenzothiophen-2-yl 1CH2—CO-1-(4-acetyl)-piperazinyl 52 3-phenylbenzothiophen-2-yl 1CH2—CONH(CH₂)₂OH 33 3-phenyl-1,4-benzodioxin-2-yl 0CH₂—CO-1-(4-acetyl)-piperazinyl 53 3-phenyl-1,4-benzodioxin-2-yl 1CH₂CO-1-(4-acetyl)-piperazinyl 3-phenyl-1,4-benzodioxin-2-yl 0CH₂CONHCH(CH₃)₂ 142 3-phenyl-1,4-benzodioxin-2-yl 1 CH₂CONHCH(CH₃)₂3-phenyl-1,4-benzodioxin-2-yl 0 CH₂CONH₂ 1433-phenyl-1,4-benzodioxin-2-yl 1 CH₂CONH₂ 6,7-dichloro-3-phenyl-1,4- 0CH₂CONH₂ benzodioxin-2-yl 144 6,7-dichloro-3-phenyl-1,4- 1 CH₂CONH₂benzodioxin-2-yl 6,7-dichloro-3-phenyl-1,4- 0CH₂CO-1-(4-acetyl)-piperazinyl benzodioxin-2-yl 1456,7-dichloro-3-phenyl-1,4- 1 CH₂CO-1-(4-acetyl)-piperazinylbenzodioxin-2-yl 148 3-phenyl-1H-indol-2-yl 0 CH₂CONH₂ 1493-phenyl-1H-indol-2-yl 1 CH₂CONH₂ 150 7-chlorodibenzofuran-1-yl 0CH₂CONH₂ 151 7-chlorodibenzofuran-1-yl 1 CH₂CONH₂8-chlorodibenzofuran-1-yl 0 CH₂CONH₂ 152 8-chlorodibenzofuran-1-yl 1CH₂CONH₂ 7,8-dichlorodibenzofuran-1-yl 0 CH₂CONH₂ 1537,8-dichlorodibenzofuran-1-yl 1 CH₂CONH₂

In a second embodiment, the present invention provides a method fortreatment of diseases comprising administering to a subject in needthereof a therapeutically effective amount of a compound of formula (A)and formula (I), or a pharmaceutically acceptable salt thereof. In apreferred embodiment, the present invention is to provide methods oftreating or preventing diseases or disorders, including treatment ofsleepiness, promotion and/or improvement of wakefulness, preferablyimprovement of wakefulness in patients with excessive sleepinessassociated with narcolepsy, sleep apnea, preferably obstructive sleepapnea/hypopnea, and shift work disorder; treatment of Parkinson'sdisease; Alzheimer's disease; cerebral ischemia; stroke; eatingdisorders; attention deficit disorder (“ADD”), attention deficithyperactivity disorder (“ADHD”); depression; schizophrenia; fatigue,preferably fatigue associated with cancer or neurological diseases, suchas multiple sclerosis and chronic fatigue syndrome; stimulation ofappetite and weight gain and improvement of cognitive dysfunction.

Preferably, when V is a bond, and W is O, S(O)_(y), or NR¹⁰, ring D issubstituted by a phenyl group.

In a third embodiment, the present invention provides a pharmaceuticalcompositions comprising the compounds of formula (A) and formula (I)wherein the compositions comprise one or more pharmaceuticallyacceptable excipients and a therapeutically effective amount of at leastone of the compounds of the present invention, or a pharmaceuticallyacceptable salt or ester form thereof.

Preferably, when V is a bond, and W is O, S(O)_(y), or NR¹⁰, ring D issubstituted by a phenyl group.

Preferably, the compounds wherein:

U is CH₂; and

Y is C₁-C₆ alkylene optionally substituted with C₁-C₆ alkylene; and

R¹ is CONH₂, or CO₂R¹¹ with R¹¹═H or C₁-C₆ alkyl are excluded.

In a fourth embodiment, the present invention provides for the use ofcompounds of formula (A) and formula (I) or pharmaceutically acceptablesalts thereof for the manufacture of a medicament for the treatment of adisease or disorder.

Preferably, when V is a bond, and W is O, S(O)_(y), or NR¹⁰, ring D issubstituted by a phenyl group.

These and other objects, features and advantages of the benzyl-thioalkylderivatives will be disclosed in the following detailed description ofthe patent disclosure.

Definitions

The following terms and expressions contained herein are defined asfollows:

As used herein, the term “about” refers to a range of values from ±10%of a specified value. For example, the phrase “about 50 mg” includes±10% of 50, or from 45 to 55 mg.

As used herein, a range of values in the form “x-y” or “x to y”, or “xthrough y”, include integers x, y, and the integers therebetween. Forexample, the phrases “1-6”, or “1 to 6” or “1 through 6” are intended toinclude the integers 1, 2, 3, 4, 5, and 6. Preferred embodiments includeeach individual integer in the range, as well as any subcombination ofintegers. For example, preferred integers for “1-6” can include 1, 2, 3,4, 5, 6, 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 2-6, etc.

As used herein “stable compound” or “stable structure” refers to acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and preferably capable offormulation into an efficacious therapeutic agent. The present inventionis directed only to stable compounds.

As used herein, the term “alkyl” refers to a straight-chain, or branchedalkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl,neopentyl, 1-ethylpropyl, 3-methylpentyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, hexyl, octyl, etc. The alkyl moiety ofalkyl-containing groups, such as alkoxy, alkoxycarbonyl, andalkylaminocarbonyl groups, has the same meaning as alkyl defined above.Lower alkyl groups, which are preferred, are alkyl groups as definedabove which contain 1 to 4 carbons. A designation such as “C₁-C₄ alkyl”refers to an alkyl radical containing from 1 to 4 carbon atoms.

As used herein, the term “alkenyl” refers to a straight chain, orbranched hydrocarbon chains of 2 to 8 carbon atoms having at least onecarbon-carbon double bond. A designation “C₂-C₈ alkenyl” refers to analkenyl radical containing from 2 to 8 carbon atoms. Examples of alkenylgroups include ethenyl, propenyl, isopropenyl, 2,4-pentadienyl, etc.

As used herein, the term “alkynyl” refers to a straight chain, orbranched hydrocarbon chains of 2 to 8 carbon atoms having at least onecarbon-carbon triple bond. A designation “C₂-C₈ alkynyl” refers to analkynyl radical containing from 2 to 8 carbon atoms. Examples includeethynyl, propynyl, isopropynyl, 3,5-hexadiynyl, etc.

As used herein, the term “alkylene” refers to a substituted orunsubstituted, branched or straight chained hydrocarbon of 1 to 8 carbonatoms, which is formed by the removal of two hydrogen atoms. Adesignation such as “C₁-C₄ alkylene” refers to an alkylene radicalcontaining from 1 to 4 carbon atoms. Examples include methylene (—CH₂—),propylidene (CH₃CH₂CH═), 1,2-ethandiyl (—CH₂CH₂—), etc.

As used herein, the term “phenylene” refers to a phenyl group with anadditional hydrogen atom removed, i.e. a moiety with the structure of:

As used herein, the terms “carbocycle”, “carbocyclic” or “carbocyclyl”refer to a substituted or unsubstituted, stable monocyclic or bicyclichydrocarbon ring system which is saturated, partially saturated orunsaturated, and contains from 3 to 10 ring carbon atoms. Accordinglythe carbocyclic group may be aromatic or non-aromatic, and includes thecycloalkyl and aryl compounds defined herein. The bonds connecting theendocyclic carbon atoms of a carbocyclic group may be single, double,triple, or part of a fused aromatic moiety.

As used herein, the term “cycloalkyl” refers to a saturated or partiallysaturated mono- or bicyclic alkyl ring system containing 3 to 10 carbonatoms. A designation such as “C₅-C₇ cycloalkyl” refers to a cycloalkylradical containing from 5 to 7 ring carbon atoms. Preferred cycloalkylgroups include those containing 5 or 6 ring carbon atoms. Examples ofcycloalkyl groups include such groups as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexl, cycloheptyl, cyclooctyl, pinenyl, andadamantanyl.

As used herein, the term “aryl” refers to a substituted orunsubstituted, mono- or bicyclic hydrocarbon aromatic ring system having6 to 12 ring carbon atoms. Examples include phenyl and naphthyl.Preferred aryl groups include unsubstituted or substituted phenyl andnaphthyl groups. Included within the definition of “aryl” are fused ringsystems, including, for example, ring systems in which an aromatic ringis fused to a cycloalkyl ring. Examples of such fused ring systemsinclude, for example, indane, indene, and tetrahydronaphthalene.

As used herein, the terms “heterocycle”, “heterocyclic” or“heterocyclyl” refer to a substituted or unsubstituted carbocyclic groupin which the ring portion includes at least one heteroatom such as O, N,or S. The nitrogen and sulfur heteroatoms may be optionally oxidized,and the nitrogen may be optionally substituted in non-aromatic rings.Heterocycles are intended to include heteroaryl and heterocycloalkylgroups.

As used herein, the term “heterocycloalkyl” refers to a cycloalkyl groupin which one or more ring carbon atoms are replaced by at least onehetero atom such as —O—, —N—, or —S—. Examples of heterocycloalkylgroups include pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl,pirazolidinyl, pirazolinyl, pyrazalinyl, piperidyl, piperazinyl,morpholinyl, thiomorpholinyl, tetrahydrofuranyl, dithiolyl, oxathiolyl,dioxazolyl, oxathiazolyl, pyranyl, oxazinyl, oxathiazinyl, andoxadiazinyl.

As used herein, the term “heteroaryl” refers to an aromatic groupcontaining 5 to 10 ring carbon atoms in which one or more ring carbonatoms are replaced by at least one hetero atom such as —O—, —N—, or —S—.Examples of heteroaryl groups include pyrrolyl, furanyl, thienyl,pirazolyl, imidazolyl, thiazolyl, isothiazolyl, isoxazolyl, oxazolyl,oxathiolyl, oxadiazolyl, triazolyl, oxatriazolyl, furazanyl, tetrazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl,isoindolyl, indazolyl, benzofuranyl, isobenzofuranyl, purinyl,quinazolinyl, quinolyl, isoquinolyl, benzoimidazolyl, benzothiazolyl,benzothiophenyl, thianaphthenyl, benzoxazolyl, benzisoxazolyl,cinnolinyl, phthalazinyl, naphthyridinyl, and quinoxalinyl. Includedwithin the definition of “heteroaryl” are fused ring systems, including,for example, ring systems in which an aromatic ring is fused to aheterocycloalkyl ring. Examples of such fused ring systems include, forexample, phthalamide, phthalic anhydride, indoline, isoindoline,tetrahydroisoquinoline, chroman, isochroman, chromene, and isochromene.

As used herein, the term “arylalkyl” refers to an alkyl group that issubstituted with an aryl group. Examples of arylalkyl groups include,but are not limited to, benzyl, bromobenzyl, phenethyl, benzhydryl,diphenylmethyl, triphenylmethyl, diphenylethyl, naphthylmethyl, etc.

As used herein, the term “amino acid” refers to a group containing bothan amino group and a carboxyl group. Embodiments of amino acids includeα-amino, β-amino, γ-amino acids. The α-amino acids have a generalformula HOOC—CH(side chain)-NH₂. In certain embodiments, substituentgroups for the compounds of the present invention include the residue ofan amino acid after removal of the hydroxyl moiety of the carboxyl groupthereof; i.e., groups of formula —C(═O)CH(NH₂)-(side chain). The aminoacids can be in their D, L or racemic configurations. Amino acidsinclude naturally-occurring and non-naturally occurring moieties. Thenaturally-occurring amino acids include the standard 20 α-amino acidsfound in proteins, such as glycine, serine, tyrosine, proline,histidine, glutamine, etc. Naturally-occurring amino acids can alsoinclude non-α-amino acids (such as β-alanine, γ-aminobutyric acid,homocysteine, etc.), rare amino acids (such as 4-hydroxyproline,5-hydroxylysine, 3-methylhistidine, etc.) and non-protein amino acids(such as citrulline, ornithine, canavanine, etc.). Non-naturallyoccurring amino acids are well-known in the art, and include analogs ofnatural amino acids. See Lehninger, A. L. Biochemistry, 2nd ed.; WorthPublishers: New York, 1975; 71-77, the disclosure of which isincorporated herein by reference. Non-naturally occurring amino acidsalso include α-amino acids wherein the side chains are replaced withsynthetic derivatives.

Representative side chains of naturally occurring and non-naturallyoccurring (X-amino acids are shown below in Table A.

TABLE A H CH₃ CH(CH₃₎ ₂ CH₂CH(CH₃)₂ CH(CH₃)CH₂CH₃ CH₂OH CH₂SH CH(OH)CH₃CH₂CH₂SCH₃ CH₂C₆H₅ (CH₂)₄NH₂ (CH₂)₃NHC(═NH)NH₂ CH₂COOH CH₂CH₂COOHCH₂CONH₂ CH₂CH₂CONH₂ CH₂CH₃ CH₂CH₂CH₃ CH₂CH₂CH₂CH₃ CH₂CH₂SH CH₂CH₂OHCH₂CH₂SCH₃ (CH₂)₃NH₂ (CH₂)₂CH(OH)CH₂NH₂ (CH₂)₃NHC(═O)NH₂(CH₂)₂ONHC(═NH)NH₂ CH₂C(═O)NHCH₂COOH

As used herein, the term “subject” refers to a warm blooded animal suchas a mammal, preferably a human, or a human child, which is afflictedwith, or has the potential to be afflicted with one or more diseases andconditions described herein.

As used herein, a “therapeutically effective amount” refers to an amountof a compound of the present invention effective to prevent or treat thesymptoms of particular disorder. Such disorders include, but are notlimited to, those pathological and neurological disorders associatedwith the aberrant activity of the receptors described herein, whereinthe treatment or prevention comprises inhibiting, inducing, or enhancingthe activity thereof by contacting the receptor with a compound of thepresent invention.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for contact withthe tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem complicationscommensurate with a reasonable benefit/risk ratio.

As used herein, the term “unit dose” refers to a single dose which iscapable of being administered to a patient, and which can be readilyhandled and packaged, remaining as a physically and chemically stableunit dose comprising either the active compound itself, or as apharmaceutically acceptable composition, as described hereinafter.

All other terms used in the description of the present invention havetheir meanings as is well known in the art.

In another aspect, the present invention is directed to pharmaceuticallyacceptable salts of the compounds described above. As used herein,“pharmaceutically acceptable salts” includes salts of compounds of thepresent invention derived from the combination of such compounds withnon-toxic acid or base addition salts.

Acid addition salts include inorganic acids such as hydrochloric,hydrobromic, hydroiodic, sulfuric, nitric and phosphoric acid, as wellas organic acids such as acetic, citric, propionic, tartaric, glutamic,salicylic, oxalic, methanesulfonic, para-toluenesulfonic, succinic, andbenzoic acid, and related inorganic and organic acids.

Base addition salts include those derived from inorganic bases such asammonium and alkali and alkaline earth metal hydroxides, carbonates,bicarbonates, and the like, as well as salts derived from basic organicamines such as aliphatic and aromatic amines, aliphatic diamines,hydroxy alkamines, and the like. Such bases useful in preparing thesalts of this invention thus include ammonium hydroxide, potassiumcarbonate, sodium bicarbonate, calcium hydroxide, methylamine,diethylamine, ethylenediamine, cyclohexylamine, ethanolamine and thelike.

In addition to pharmaceutically-acceptable salts, other salts areincluded in the invention. They may serve as intermediates in thepurification of the compounds, in the preparation of other salts, or inthe identification and characterization of the compounds orintermediates.

The pharmaceutically acceptable salts of compounds of the presentinvention can also exist as various solvates, such as with water,methanol, ethanol, dimethylformamide, ethyl acetate and the like.Mixtures of such solvates can also be prepared. The source of suchsolvate can be from the solvent of crystallization, inherent in thesolvent of preparation or crystallization, or adventitious to suchsolvent. Such solvates are within the scope of the present invention.

The present invention also encompasses the pharmaceutically acceptableprodrugs of the compounds disclosed herein. As used herein, “prodrug” isintended to include any compounds which are converted by metabolicprocesses within the body of a subject to an active agent that has aformula within the scope of the present invention. Since prodrugs areknown to enhance numerous desirable qualities of pharmaceuticals (e.g.,solubility, bioavailability, manufacturing, etc.) the compounds of thepresent invention may be delivered in prodrug form. Conventionalprocedures for the selection and preparation of suitable prodrugderivatives are described, for example, in Prodrugs, Sloane, K. B., Ed.;Marcel Dekker: New York, 1992, incorporated by reference herein in itsentirety

It is recognized that compounds of the present invention may exist invarious stereoisomeric forms. As such, the compounds of the presentinvention include both diastereomers and enantiomers. The compounds arenormally prepared as racemates and can conveniently be used as such, butindividual enantiomers can be isolated or synthesized by conventionaltechniques if so desired. Such racemates and individual enantiomers andmixtures thereof form part of the present invention.

It is well known in the art how to prepare and isolate such opticallyactive forms. Specific stereoisomers can be prepared by stereospecificsynthesis using enantiomerically pure or enantiomerically enrichedstarting materials. The specific stereoisomers of either startingmaterials or products can be resolved and recovered by techniques knownin the art, such as resolution of racemic forms, normal, reverse-phase,and chiral chromatography, recrystallization, enzymatic resolution, orfractional recrystallization of addition salts formed by reagents usedfor that purpose. Useful methods of resolving and recovering specificstereoisomers described in Eliel, E. L.; Wilen, S. H. Stereochemistry ofOrganic Compounds; Wiley: New York, 1994, and Jacques, J, et al.Enantiomers, Racemates, and Resolutions; Wiley: New York, 1981, eachincorporated by reference herein in their entireties.

It is further recognized that functional groups present on the compoundsof Formula I may contain protecting groups. For example, the amino acidside chain substituents of the compounds of Formula I can be substitutedwith protecting groups such as benzyloxycarbonyl or t-butoxycarbonylgroups. Protecting groups are known per se as chemical functional groupsthat can be selectively appended to and removed from functionalities,such as hydroxyl groups and carboxyl groups. These groups are present ina chemical compound to render such functionality inert to chemicalreaction conditions to which the compound is exposed. Any of a varietyof protecting groups may be employed with the present invention.Preferred protecting groups include the benzyloxycarbonyl (Cbz; Z) groupand the tert-butyloxycarbonyl (Boc) group. Other preferred protectinggroups according to the invention may be found in Greene, T. W. andWuts, P. G. M., Protective Groups in Organic Synthesis, 2d. Ed., Wiley &Sons, 1991.

Synthesis

The compounds of the present invention may be prepared in a number ofmethods well known to those skilled in the art, including, but notlimited to those described below, or through modifications of thesemethods by applying standard techniques known to those skilled in theart of organic synthesis. All processes disclosed in association withthe present invention are contemplated to be practiced on any scale,including milligram, gram, multigram, kilogram, multikilogram orcommercial industrial scale.

It will be appreciated that the compounds of the present invention maycontain one or more asymmetrically substituted carbon atoms, and may beisolated in optically active or racemic forms. Thus, all chiral,diastereomeric, racemic forms and all geometric isomeric forms of astructure are intended, unless the specific stereochemistry or isomericform is specifically indicated. It is well known in the art how toprepare such optically active forms. For example, mixtures ofstereoisomers may be separated by standard techniques including, but notlimited to, resolution of racemic forms, normal, reverse-phase, andchiral chromatography, preferential salt formation, recrystallization,and the like, or by chiral synthesis either from active startingmaterials or by deliberate chiral synthesis of target centers.

As will be readily understood, functional groups present on thecompounds of Formula I may contain protecting groups. For example, theamino acid side chain substituents of the compounds of Formula I can besubstituted with protecting groups such as benzyloxycarbonyl ort-butoxycarbonyl groups. Protecting groups are known per se as chemicalfunctional groups that can be selectively appended to and removed fromfunctionalities, such as hydroxyl groups and carboxyl groups. Thesegroups are present in a chemical compound to render such functionalityinert to chemical reaction conditions to which the compound is exposed.Any of a variety of protecting groups may be employed with the presentinvention. Preferred protecting groups include the benzyloxycarbonyl(Cbz; Z) group and the tert-butyloxycarbonyl (Boc) group. Otherpreferred protecting groups according to the invention may be found inGreene, T. W. and Wuts, P. G. M., “Protective Groups in OrganicSynthesis” 2d. Ed., Wiley & Sons, 1991.

The general routes to prepare the examples shown in Table 1 of thepresent invention are shown in scheme A and in scheme B. The reagentsand starting materials are commercially available, or readilysynthesized by well-known techniques by one of ordinary skill in thearts. All substituents in the synthetic Schemes, unless otherwiseindicated, are as previously defined.

Step 1: Synthesis of Compounds of General Structure Ia Wherein q is 0

Compounds of general formula Ia may be synthetized via routes A, B, C orD respectively.

Route A:

An appropriate aryl or heteroaryl, optionally substituted, of generalformula A wherein Ar is as defined in the final product is reacted withan appropriate compound of general formula D wherein Y and R¹ are asdefined, in a non-polar solvent as methylenechloride and like (CHCl₃,CS₂, CCl₄) in presence of a lewis acid like Sn Cl₄, AlCl₃, ZnI₂ at 0°C., under a nitrogen atmosphere to give compound Ia wherein Ar, Y and R¹are as defined. Upon completion, the reaction mixture is concentratedand compound Ia, is isolated by conventional methods commonly employedby those skilled in the art.

Optionally, ester of general structure Ia (R¹=COOR) prepared previouslymay be hydrolysed in a presence of an inorganic base M-OH as NaOH, LiOH,NH₄OH and the like to obtain the corresponding acid Ia (R¹=COOH).

Route B:

In Step 1a, the appropriate compound B wherein Ar is as defined in thefinal product, dissolved in a aprotic solvent as chloroform and like(CH₂Cl₂, Toluene, CCl₄ . . . ) is be treated with thioacetamide, at atemperature between 60 and 100° C., preferably at reflux, for a periodof time in the 2 to 5 hours range. The reaction mixture is cooled toroom temperature (in some cases, an ice-bath might be needed) and theprecipitated solid is optionally filtered and thoroughly washed withmethylenechloride to generate the appropriate E.

In Step 1b, compound E undergoes a substitution reaction with anappropriate compound G of structure LG-Y—R¹ wherein 3Y and R¹ are asdefined and LG is an appropriate leaving group (for example an halogeneatom as Cl, Br) to generate compounds of general structure Ia whereinq=0, Y and R¹ are as defined.

Optionally, the ester of general structure Ia (R¹=COOR) preparedpreviously may be hydrolysed in a presence of an inorganic base M-OH asNaOH, LiOH, NH₄OH and the like to obtain the corresponding acid Ia(R¹=COOH).

Route C:

In Step 1a, the alcohol moiety of an appropriate compound C wherein Aris as defined in the final product is converted to the correspondingthiouronium salt of general formula F.

In an aspect, the compound F is formed by reacting a compound C withthiourea and a suitable acid. Suitable acids include but are not limitedto mineral acids, such as hydrobromic acid, hydrochloric acid, sulfuricacid.

For example, in Step 1a, an appropriate amount of thiourea in 48% HBrand water is warmed (preferably to 60-70° C.), followed by addition ofcompound C. The reaction mixture is refluxed and the stirring iscontinued for an additional period of time for completion of thereaction. The reaction mixture is cooled to room temperature (in somecases, an ice-bath might be needed) and the precipitated solid isoptionally filtered and thoroughly washed with water to generate theappropriate thiouronium salt. Sometimes, there is an oil in place of thesolid: in that case, the oil is thoroughly washed with water bydecantation and used directly in Step 1b.

In Step 1b, the thiouronium salt is first converted into thecorresponding thiol which further undergoes a substitution reaction withan appropriate reactant of generic structure structure LG-Y—R¹ (compoundG) wherein Y and R¹ are as defined and LG is a suitable leaving group(for example an halogene atom as Cl, Br) to generate the correspondingcompound Ia wherein q=0 and Y and R¹ are as defined.

As an example the wet solid of structure F (or the oil with someremaining water) from the previous step is taken into additional waterand treated with an aqueous base, preferably sodium hydroxide solution.The mixture is warmed preferably to 70-80° C., but in some cases ahigher temperature might be needed) and to it an appropriate amount ofLG-Y—R¹ in water (or in some cases, an alcoholic solvent) is added. Thereaction mixture is refluxed for an appropriate period of time, cooled,taken into water and washed with an organic solvent (preferably ether).The basic aqueous layer is acidified with an inorganic acid solution(e.g. aqueous HCl solution). The aqueous (acidic) solution is thenextracted several times into an organic solvent (e.g. ether or ethylacetate). The combined organic layer is washed with brine, dried (MgSO₄or Na₂SO₄) and concentrated to give the crude product that may be useddirectly in the next step. However, purification could be achieved byemploying known purification techniques (e.g. recrystallization orcolumn chromatography) to provide pure compound Ia wherein q is 0, Y andR¹ are as defined in the final product.

Route D:

In Step 1c, compound C wherein Ar is as defined in the final product isconverted to the corresponding compound Ia by reacting with aappropriate thio derivative of general structure H wherein Y and R¹ areas defined in the final product Ia in the presence of ZnI₂.Appropriately, the reaction may be conducted under a nitrogenatmosphere.

Alternatively, compound Ia wherein R¹ is COOH may be converted into thecorresponding alkyl ester R¹ is COOR using methods known by peopleskilled in the art.

Route E:

A solution of compound of general formula B, wherein Ar is as defined inthe final product, is reacted at 40 to 100° C. with an appropriatecompound of general formula H wherein Y and R¹ are as defined, in apolar aprotic solvent as DMF and alkalin mixture. Upon completion, thereaction mixture is concentrated and compound Ia, is isolated byconventional methods commonly employed by those skilled in the art.

Step 2: Synthesis of Compounds of General Structure Ib Wherein q is 1 or2

Compounds of structure Ia wherein q=0 may optionally be oxidized togenerate compounds of structure Ib wherein q is 1 or 2. Compound Ibwherein q is 1 is prepared under mild oxidation conditions by reactingcompound Ia wherein q is 0 in an appropriate solvent with an appropriateoxidizing agent. An appropriate oxidizing agent is one that oxidizes thesulphide group of compound Ia. The corresponding product is isolated andpurified by methods well known in the art.

For example, to solution of compound Ia in acetic acid, an appropriateoxidizing agent (e.g. 30% ww H₂O₂, 1 equivalent) in the acetic acid isslowly added. Stirring is continued at low temperature until thedisappearance of the starting material, as evidenced by variousanalytical techniques. The reaction mixture is concentrated. The desiredproduct (compound Ib wherein q is 1) is purified, if needed, byemploying known purification techniques (preferably by columnchromatography and/or crystallization). In some cases, the oxidation isperformed by employing 50% H₂O₂ in glacial acetic acid solvent.

Compound of formula Ib wherein q=2, may be obtained under more drasticreaction conditions such as H₂O₂ (more than 2 equivalents) in acidicmedium, under heating, preferably at temperature comprise between roomtemperature and the boiling temperature of the solvent, preferablybetween 40 and 60° C., for a time sufficient to obtain the desiredproduct, usually approximately between 2 and 10 hours, preferablyapproximately 8 hours.

Compound Ia were prepared according to the general procedures describedfor Step 1 in Scheme A. Then two different synthetic routes mayoptionally be used to generate compounds Id

wherein R¹ is C(═O)NR¹²R¹³.

Step 2: Synthesis of Compounds of General Structure Ic Wherein q=0:

In Step 2, the appropriate carboxylic ester of general formula Iawherein q=0 and R is alkyl is reacted with an appropriate amine ofgeneral structure NHR¹²R¹³ and converted into the corresponding amide ofgeneral formula Ic wherein q=0, Y, Ar and R¹² and R¹³ are as defined inthe final product. May be used aqueous ammonium hydroxide (28%) ormethanolic solution of ammonia or ammonia gas to give the desiredcompound Ic wherein R¹²=R¹³=H.

Alternatively, in Step 2, the appropriate carboxylic acid of generalformula Ia wherein q=0 and R═H may be reacted with an appropriate amineof general formula NH R¹²R¹³, a coupling reagent such as EDCl or DCCl,or a polymer supported coupling reagent (N-cyclohexyl carbodiimide), andoptionally HOBT in an aprotic solvent as methylene chloride and like toprovide amide of general formula Ic wherein q=0. An appropriate amine isone which correlates to R¹² and R¹³ as defined in the final product. Insome cases, when the appropriate amide bears a protecting group as thetert-butyloxycarbonyl (“Boc”) and like on a second nitrogen group, theprotected group is further removed in a subsequent step. De-protectionof “Boc” may be performed at room temperature by acid treatment such as4N HCl in 1,4-dioxane or trifluoroacetic acid in CH₂Cl₂.

Step 3: Synthesis of Compounds of General Structure Id Wherein q=1 or 2:

Compounds of structure Ic wherein q=0 may optionally be oxidized togenerate compounds of structure Id wherein q=1 or 2 according to theprocedure described previously in Scheme A Step 2.

Alternatively, in Step 2, compound Ia wherein q=0 may be oxidized togenerate the corresponding compound of general structure Ib wherein q=1or 2, which, in turn, is amidified appropriately to give raise tocompound Id in Step 3 of scheme B.

EXAMPLES

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments. These examples aregiven for illustration of the invention and are not intended to belimiting thereof.

1) Synthesis of Compounds B Synthesis of 2-Bromomethyl-dibenzofuran 1a

Compound 1a:

A mixture of dibenzofuran (93.5 g, 0.557 M), trioxane (20 g, 0.222 M)and myrystyltrimethylammonium bromide (6.2 g, 18.5 mmol) in 1 L aceticacid and 135 mL of 48% HBr was stirred at 50-60° C. for 28 h, thenconcentrated; the residue was dissolved in CH₂Cl₂, washed with water,dried over Na₂SO₄, evaporated to give the crude bromide 1a. Compound 1awas used without further purification in the next step.

Synthesis of 7-chloro-1-bromomethyl-dibenzofuran 1b,8-chloro-1-bromomethyl-dibenzofuran 1c and7,8-dichloro-1-bromomethyl-dibenzofuran 1d

1) Synthesis of 2,4-dichloro-benzenesulfonic acid2-amino-3-methyl-phenyl ester

To a mixture of 2,4-dichlorobenzenesulfonyl chloride (20.2 g, 82.3 mmol)and 2-amino-m-cresol (11 g, 89.4 mmol) in 200 mL of methylene chloride,triethylamine (8.5 g, 83.4 mmol) was added dropwise at 5° C. The mixturewas stirred at ambient temperature for 16 hours.

The reaction was quenched by water (500 mL), the organic phase washed bywater, dried over Na₂SO₄ and evaporated. The residue was purified byflash chromatography (CH₂Cl₂) to give 26.2 g of an orange oil thatcrystallized on stand.

1H NMR (400 MHz, CHCl₃) δ 2.2 (3H, s), 3.98 (2H, bs), 6.51 (1H, t), 6.75(1H, d), 6.98 (1H, d), 7.4 (1H, d), 7.65 (1H, s), 7.98 (1H, d).

2) Synthesis of diazonium salt of 2,4-dichloro-benzenesulfonic acid2-amino-3-methyl-phenyl ester

To a suspension of 2,4-dichloro-benzenesulfonic acid2-amino-3-methyl-phenyl ester (26.2 g, 78.9 mmol) in absolute ethanol(200 ml), was added the tetrafluoroboric acid-dimethylether complex(21.5 g, 160 mmol) at 5° C. under nitrogen to give a solution, then asolution of isoamyl nitrite (11.6 g, 95.2 mmol) in 80 mL ethanol wasadded dropwise during 20 minutes to give a suspension. The mixture wasstirred and kept at 5° C. for one hour, and then the suspension wasfiltered, washed with ether, dried under vacuum to give 32.9 g of thediazonium slat as a white powder.

This compound is pure enough for the next step.

3) Synthesis of 2′,4′-dichloro-6-methyl-biphenyl-2-ol

To a suspension of the diazonium (32.9 g, 76.2 mmol) in 280 mL ofacetone, was added dropwise a solution of TiCl₃ in aqueous HCl (>10% wtin 20-30% wt HCl, 250 mL) at 5° C. during 30 minutes. The reaction wasmaintained for additional 2 hours, then diluted with 300 mL of water andextracted by methylenechloride (2×200 mL). The combined extracts werewashed with water, dried over Na₂SO₄, evaporated to give the crudeproduct which was purified twice by flash chromatography(cyclohexane/ethyl acetate, 5/1) to 16.5 g of a yellowish oil.

1H NMR (400 MHz, CHCl₃) δ 2.05 (3H, s), 4.55 (1H, s), 6.75 (1H, d), 6.85(1H, d), 7.2 (2H, m), 7.4 (1H, dd), 7.65 (1H, s).

4) Synthesis of 7-chloro-1-methyl-dibenzofuran

A mixture of 2′,4′-dichloro-6-methyl-biphenyl-2-ol (8.75 g, 34.7 mmol),K₂CO₃ (25 g, 180 mmol) and CuO (17 g, 214 mmol) in 200 mL of pyridinewas refluxed under nitrogen for 2 hours. Pyridine was eliminated bydistillation. To the residue were added 200 mL of water and 200 mL ofmethylenechloride, the resulting mixture was filtered through Celite.The organic phase was washed with water, dried over Na₂SO₄ andevaporated. The residue was purified by flash chromatography(cyclohexane/ethyl acetate, 5/1) to give 6.27 g of beige solid.

1H NMR (400 MHz, CHCl₃) δ 2.76 (3H, s), 7.12 (1H, d), 7.4 (3H, m), 7.5(1H, d), 7.95 (1H, s).

5) Synthesis of 7-chloro-1-bromomethyl-dibenzofuran: 1b

A mixture of 7-chloro-1-methyl-dibenzofuran (6.27 g, 29.1 mmol),N-bromosuccinimide (5.4 g, 30.3 mmole) and dibenzoyl peroxide (0.82 g,3.4 mmole) in tetrachlorocarbon (100 mL) was heated at reflux for 3hours, and then concentrated to about 50 mL. The resulting suspensionwas filtered, rinsed by CCl₄. The solid was dissolved in CH₂Cl₂, washedby water, dried over Na₂SO₄, evaporated to give 6.16 g of beige solid.

1H NMR (400 MHz, CHCl₃) δ 4.95 (2H, s), 7.32 (1H, d), 7.4 (2H, m), 7.55(1H, d), 7.62 (1H, d), 8.03 (1H, d).

Compounds 1c and 1d

Compounds 1c and 1d were synthetized according to the protocol describedfor compound Ib

-   -   4.1 g of 8-chloro-1-bromomethyl-dibenzofuran 1c were obtained        using 2,5-dichlorobenzenesulfonyl chloride (20.2 g, 82.3 mmol)        and 2-amino-m-cresol (11 g, 89.4 mmol) as starting material.

1H NMR (400 MHz, CHCl₃) δ:4.95 (2H, s), 7.32 (1H, d), 7.4 (2H, m), 7.53(2H, m), 8.1 (1H, s).

-   -   8.7 g of 7,8-dichloro-1-bromomethyl-dibenzofuran 1d were        obtained using 2,4,5-trichlorobenzenesulfonyl chloride (20.2 g,        82.3 mmol) and 2-amino-m-cresol (11 g, 89.4 mmol) as starting        material.

1H NMR (400 MHz, CHCl₃) δ: 4.95 (2H, s), 7.3 (1H, d), 7.43 (H, t), 7.53(1H, m), 7.72 (1H, d), 8.2 (1H, s).

2) Synthesis of Compounds C Synthesis of(3-Phenyl-benzo[b]thiophen-2-yl)-methanol 3

Compound 2: Synthesis of (3-Phenyl-benzo[b]thiophen-2-yl)-carboxylicacid

To a mixture of 3,3-diphenylpropionic acid (20 g, 88.5 mmol) in 9 mLpyridine was added 8 mL SOCl₂ at room temperature. The resulting mixturewas heated to 150-160° C., then additional 23 mL SOCl₂ were addeddropwise during 1 h to give a brownish solution, the reaction wasstirred at reflux for 2 h, cooled, poured into a mixture of H₂O/conc.HCl/THF (100 mL/10 mL/150 mL). The mixture was refluxed for 3 h thencooled. The organic layer was separated, washed with brine, dried overMgSO₄ and concentrated, the residue was treated with 200 mL ethyl ether,filtered and the filtrate concentrated. The crude product wascrystallized in toluene to furnish 10 g of compound 2.

1H NMR (400 MHz, CHCl₃) δ 7.38 (3H, m), 7.5 (5H, m), 7.89 (1H, dd).

Compound 3: Synthesis of 3-Phenyl-benzo[b]thiophen-2-yl)-methanol

To a mixture of compound 2 (21.9 g, 86 mmol) in 300 mL dry THF, wasadded dropwise a solution of 1 M BH₃-THF (105 mL, 105 mmol) at roomtemperature under N₂ during 15 minutes. The mixture was stirred at roomtemperature for 18 h, and then quenched by brine. The separated organiclayer was washed with brine, dried over MgSO₄ and concentrated. Thecrude product was purified by flash chromatography (CH₂Cl₂/methanol,100/1) yielding 17.2 g of compound 3 as a colorless oil thatcrystallized on stand.

1H NMR (400 MHz, CHCl₃) δ 2 (1H, bs), 4.83 (2H, s), 7.33 (2H, m), 7.4(3H, m), 7.5 (2H, m), 7.6 (1H, d), 7.82 (1H, dd).

Synthesis of (2-Phenyl-benzofuran-3-yl)-methanol 7

Compound 4

A mixture of phenol (23.6 g, 0.25 M), 2-bromoacetophenone (50 g, 0.25 M)and K₂CO₃ (35 g, 0.25 M) in 150 mL of acetone was refluxed for 4 h,cooled, poured into 1.5 L of water to give a suspension. The solid wascollected by filtration, then crystallized in ethanol, dried undervacuum to give 33 g of compound 4 as a beige powder.

Compound 5

To 150 mL of polyphosphoric acid heated at 130-140° C., was addedcompound 4 (20 g, 94.3 mmol), the reaction was kept at 130-140° C. for 3h and then poured into 1 L of water. The solid was filtered, rinsed withwater, dried in vacuum to give crude product that was crystallized inethanol to afford 12.2 g of compound 5 as a yellow crystal.

1H NMR (400 MHz, CHCl₃) δ 7.05 (1H, s), 7.25 (2H, m), 7.35 (1H, m), 7.45(2H, t), 7.5 (1H, d), 7.6 (1H, d), 7.85 (2H, d).

Compound 6

POCl₃ (10.5 mL, 112.5 mmol) was added to DMF (21 mL at 0-5° C.). Themixture was stirred at room temperature for 10 minutes, then compound 5(4 g, 20.6 mmol) was added portionwise. The resultant mixture was heatedat 80-90° C. for 5 h, stirred overnight at room temperature, poured onice, and then extracted into CH₂Cl₂, the organic layer was washed withwater, dried over MgSO₄, concentrated to give an oil. The crude productwas purified by flash chromatography (cyclohexane/ethyl acetate, 5/1) toafford 3.3 g of compound 6 as a yellow solid.

1H NMR (400 MHz, CHCl₃) δ: 7.4 (2H, m), 7.55 (4H, m), 7.83 (2H, m), 8.25(1H, m), 10.33 (1H, s).

Compound 7

To a solution of compound 6 (3.16 g, 14.2 mmol) in 30 mL of 2-propanoland 20 mL of THF, NaBH₄ (0.8 g, 21.1 mmol) was added at roomtemperature. 10 minutes later, the reaction mixture was concentrated andquenched with water. The resulting precipitate was filtrated, driedunder vacuum to furnish 3.19 g of pure compound 7.

1H NMR (400 MHz, CHCl₃) δ 4.95 (2H, d), 7.25 (2H, m), 7.45 (1H, m), 7.5(3H, m), 7.7 (1H, d), 7.85 (2H, d).

Synthesis of (9H-Fluoren-1-yl)-methanol 9

Compound 8

A mixture of 9-fluorenone-1-caboxylic acid (6 g, 26.8 mmol), a 55% HIsolution HI (10.5 mL) and red phosphorous (9,6 g, 310 mmol) in 400 mLacetic acid was refluxed for 48 h, then concentrated. Following additionof 200 mL of water; the mixture was stirred overnight and filtered. Thecake was treated in 200 mL water and 5 mL concentrated NaOH and filteredto remove residual phosphorous. The filtrate was adjusted to pH 2 with 4N HCl to give a suspension that was filtered, washed with, dried invacuum to afford 5.47 g of compound 8 as a beige solid.

1H NMR (400 MHz, DMSO-d₆) δ 4.25 (2H, s), 7.35 (2H, m), 7.55 (1H, t),7.63 (1H, d), 7.92 (1H, d), 7.96 (1H, d), 8.2 (1H, d).

Compound 9

To a slurry of compound 8 (5.47 g, 26 mmol) in 50 mL dry THF, was addeddropwise a 1 M solution BH₃-THF (28 mL) at room temperature over a 35minutes period. The mixture was stirred at room temperature for 16 hthen quenched by brine. The organic layer was washed with brine, driedover MgSO₄, concentrated to give 4.5 g of compound 2 as a yellow solid.

1H NMR (400 MHz, CHCl₃) δ 3.9 (2H, s), 4.85 (2H, s), 7.35 (4H, m), 7.55(1H, d), 7.75 (1H, d), 7.8 (1H, d).

Synthesis of (9H-Fluoren-2-yl)-methanol 10

Compound 10

Compound 10 was prepared according to the process described for as for3-hydroxymethyl-2-phenyl-benzofuran 7.

Reagents: Fluorene-2-carboxaldehyde (5.57 g, 28.7 mmol) and NaBH₄ (1.6g, 42.3 mmol).

1H NMR (400 MHz, CHCl₃) δ 3.9 (2H, s), 4.75 (2H, s), 7.3 (3H, m), 7.55(2H, m), 7.75 (2H, t).

Synthesis of (9H-Fluoren-4-yl)-methanol 13

Compound 11

To 200 mL of concentrated H₂SO₄, was added biphenic acid (70 g, 0.289M). The resulting mixture was heated to 140° C. for 20 minutes, cooled,poured into ice-water (2 L) to give a suspension. The mixture wasfiltered, washed with water, dried at 50° C. under vacuum to afford 56 gof compound 11 as greenish yellow solid.

1H NMR (400 MHz, DMSO-d₆) δ: 7.45 (2H, m), 7.65 (2H, q), 7.8 (1H, d),7.95 (1H, d), 8.25 (1H, d).

Compound 12

Compound 12 was prepared according to the procedure described for9-fluorenone-1-caboxylic acid 9.

Reagents: Compound 11 (22.4 g, 0.1 M), red phosphorous (35.8 g, 1.15 M)and 58% HI (39 ml).

1H NMR (400 MHz, CHCl₃) δ 3.95 (2H, s), 7.4 (3H, m), 7.55 (H, d), 7.75(1H, d), 8.05 (1H, d), 8.6 (1H, d).

Compound 13

Compound 13 was synthesized in a manner substantially the same as for3-hydroxymethyl-2-phenyl-benzofuran 8

Reagents: Compound 12 (9.66 g, 49.3 mmol) and NaBH (1.9 g, 48.7 mmol).

1H NMR (400 MHz, CHCl₃) δ 2.13 (1H, t), 5.1 (2H, d), 7.33 (2H, m), 7.5(2H, m), 7.6 (1H, d), 7.9 (1H, d), 7.95 (1H, d).

Dibenzofuran-4-yl-methanol 16 and dibenzothiophen-4-yl-methanol 17

Compound 14

To a solution of dibenzofuran (6.2 g, 36.9 mmol) in 100 mL dry THF, wasadded a solution of 1.6 M n-BuLi in hexane (26 mL, 41.6 mmol) at 5° C.under a N₂ atmosphere over a 30 minutes period. The resulting solutionwas stirred at 5° C. for 1 h, then DMF (3.2 mL, 41.6 mmol) was added andstirring maintained for 20 minutes at room temperature before addingbrine. The organic layer was washed with, dried over MgSO₄ andconcentrated. The crude product was recrystallized in 2-propanol tofurnish 3.82 g of compound 14 as a yellow crystal.

1H NMR (400 MHz, CHCl₃) δ 7.4 (1H, t), 7.46 (1H, t), 7.53 (1H, t), 7.7(1H, d), 7.95 (2H, dd), 8.2 (1H, d), 10.58 (1H, s).

Compound 15

Compound 15 was prepared according to the procedure described forcompound 14.

Reagents: dibenzothiophene (36.8 g, 226 mmol) and 1.6 M n-BuLi in hexane(140 mL, 224 mmol), DMF (16.5 g, 226 mmol)

1H NMR (400 MHz, CHCl₃) δ 7.53 (2H, m), 7.68 (1H, t), 7.97 (1H, m), 7.99(1H, dd), 8.22 (1H, m), 8.44 (1H, dd), 10.3 (1H, s).

Compound 16

Compound 16 was synthesized in a manner substantially the same as for3-hydroxymethyl-2-phenyl-benzofuran 7

Reagents: Compound 14 (9.66 g, 49.3 mmol) and NaBH₄ (1.9 g, 48.7 mmol).

1H NMR (400 MHz, CHCl₃) δ 2.13 (1H, t), 5.1 (2H, d), 7.33 (2H, m), 7.5(2H, m), 7.6 (1H, d), 7.9 (1H, d), 7.95 (1H, d).

Compound 17

Compound 17 was prepared according to the procedure described forcompound 16

Reagents: compound 15 (22.2 g, 104.7 mmol) and NaBH₄ (4.5 g, 118 mmol)

1H NMR (400 MHz, CHCl₃) δ 1.95 (1H, t), 5 (2H, d), 7.5 (4H, m), 7.87(1H, m), 8.1 (1H, m), 8.2 (1H, m).

Synthesis of Dibenzothiophen-2-yl-methanol 19

Compound 18

To a solution of 2-bromodibenzofuran (33.7 g, 0.128 M) (Bull. Soc. Chim.Fr, 1973, 11, 3110-3115) in 300 mL of dry ethyl ether, a solution of 1.6M n-BuLi in hexane (85 mL, 0.136 M) was added at 5° C. under N₂ over a30 minutes period, followed by the addition of DMF (10 g, 0.137 M). Themixture was stirred at room temperature for 40 minutes, then a saturatedsolution of NH₄Cl (300 mL) was added. The organic layer was washed withbrine, dried over Na₂SO₄ and concentrated. The crude product wasrecrystallized in ethanol to furnish 25.9 g of compound 18 as a yellowcrystal.

1H NMR (400 MHz, CHCl₃) δ 7.55 (2H, m), 7.87 (1H, m), 8.0 (2H, m), 8.25(1H, m), 8.7 (1H, s), 10.2 (1H, s).

Compound 19

Compound 19 was synthesized in a manner substantially the same as for3-hydroxymethyl-2-phenyl-benzofuran 7.

Reagents: Compound 18 (20.6 g, 97.2 mmol) and NaBH₄ (4 g, 105.8 mmol).

1H NMR (400 MHz, CHCl₃) δ 4.86 (2H, s), 7.5 (3H, m), 7.86 (2H, m), 8.25(1H, m), 8.2 (2H, m).

Synthesis of Substituted dibenzofuran-2-yl-methanol 44

Compounds 20 and 26

A mixture of 4-fluorophenol (41.3 g, 0.37 M), 4-fluorobenzaldehyde (45.7g, 0.37 M) and K₂CO₃ (55 g) in 450 mL DMF was refluxed for 4 h, cooled,poured into ice water (1.5 L) to give a suspension. The mixture wasfiltered, washed with water, dried at 50° C. under vacuum to generate78.3 g of the aldehyde 20 as a brownish solid. This compound wasslurried in 2-propanol (1 L), then NaBH₄ (14 g, 0.378 M) was addedportionwise at room temperature. The resulting mixture was stirred atroom temperature for 1 h, then concentrated. The residue was poured intowater (1.5 L) to give a suspension. After filtration, the resultingsolid, washed with water, dried at 50° C. under vacuum to give 76 g of4-fluorophenoxybenzyl alcohol 26 as a yellowish crystal.

1H NMR (400 MHz, CHCl₃) δ 4.67 (2H, d), 7.0 (6H, m), 7.33 (2H, d).

Compound 32

To a solution of compound 26 (21.8 g, 0.1 M) and triethylamine (14 mL,0.1 M) in 300 mL CH₂Cl₂, acetyl chloride (8 g, 0.102 M) was added atroom temperature. The mixture was kept at room temperature for 18 h,then washed with water, dried over Na₂SO₄, concentrated to afford 27.3 gof 4-chlorophenoxybenzyl acetate 32 as an oil.

1H NMR (400 MHz, CHCl₃) δ 2.1 (3H, s), 5.05 (2H, s), 6.93 (2H, d), 7.0(4H, m), 7.3 (2H, d).

Compound 38

A brownish mixture of 32 (22.2 g, 85.4 mmol) and palladium acetate (35g, 156 mmol) in acetic acid (250 mL) was refluxed for 18 h, thenfiltered on Celite to eliminate palladium. The filtrate was concentratedto dryness. The crude producte was purified by flash chromatography(cyclohexane/ethyl acetate, 5/1) to generate 17.6 g of8-fluoro-2-acetoxymethyldibenzofuran 38 as an off-white solid.

1H NMR (400 MHz, CHCl₃) δ 2.1 (3H, s), 5.2 (2H, s), 7.12 (1H, tt), 7.46(2H, m), 7.5 (1H, d), 7.56 (1H, dd), 7.73 (1H, s).

Compound 44

To a suspension of 38 (10.3 g, 40 mmol) in 150 mL of methanol and 50 mLof water, LiOH monohydrate (3.5 g, 83.3 mmol) was added at roomtemperature. The mixture was stirred at 50° C. for 30 minutes,concentrated. The mixture was quenched with water (200 mL) to give asuspension that was filtered, washed with water, dried at 50° C. undervacuum to give 8.4 g of 8-fluoro-2-hydroxymethyldibenzofuran 44 as awhite crystal.

1H NMR (400 MHz, DMSO-d₆) δ 4.7 (2H, s), 7.33 (1H, m), 7.5 (1H, d), 7.67(1H, d), 7.7 (1H, m), 8.03 (1H, dd), 8.11 (1H, s).

Compounds 45 to 49

Compounds 45 to 49 were processed according to the procedure describedfor compound 44.

Synthesis of Dibenzofuran-1-yl-methanol 54 anddibenzofuran-3-yl-methanol 53

Compounds 51 and 52

A mixture of 3-phenoxybenzyl acetate 50 (21.8 g, 90 mmol) (prepared byacetylation of commercial 3-phenoxybenzyl alcohol) and palladium acetate(40 g, 179 mmol) in acetic acid (300 mL) was refluxed for 6 h, cooledand filtered. The filtrate was evaporated to dryness and the residuetreated with 100 mL of a mixture cyclohexane/ethyl acetate (6/1) andfiltered. The filtrate was concentrated to give a colored oil which waspurified by chromatography on silica gel (cyclohexane/ethyl acetate,6/1) to afford pure dibenzofuran-3-yl-methyl acetate 51 (3.4 g) and amixture of dibenzofuran-3-yl-methyl acetate 51 (Rf=0.6) anddibenzofuran-1-yl-methyl acetate 52 contaminated with compound 51 (Rf ofcompound 52=0.53) (8.4 g) as a white solid.

52 will be used without any further purification in the next step

Compound 51: 1H NMR (400 MHz, CHCl₃) δ 2.15 (3H, s), 5.3 (2H, s), 7.33(2H, t), 7.45 (1H, t), 7.56 (1H, d), 7.59 (1H, s), 7.96 (1H, t).

Compounds 53 and 54

Acetyl group of Compound 51 is further removed to give pure compound 53using the same procedure as described for preparation of compound 44.

Starting from 52 (contaminated by some isomer 5), a mixture of 53 and 54was prepared according to the same method.

Compound 53: 1H NMR (400 MHz, CHCl₃) δ 2.0 (1H, bs), 4.84 (2H, s), 7.45(1H, t), 7.53 (1H, d), 7.59 (1H, s), 7.92 (2H, dd).

Synthesis of (3-Phenyl-benzo[1,4]dioxin-2-yl)-methanol 59a and(6,7-Dichloro-3-phenyl-benzo[1,4]dioxin-2-yl)-methanol 59b

Compound 55

Compound 55 was prepared according to the procedure described in OrganicProcess Research & Development, 5(2), 2001, 116-121.

Reagents: 1,4-benzodioxane (10 g, 73.4 mmol), N-chlorosuccinimide (20.6g, 154 mmol) and acetic acid (20 mL).

Yield=68% (m=10.2 g).

¹H NMR (400 MHz, CDCl₃) δ 4.3 (4H, s), 6.95 (2H, s).

Compound 56a (X=H)

Compound 56a was prepared according to the procedure described inSynthesis, 1977, 755 and Tetrahedron, 46(3), 1990, 921-934.

Reagents: 1,4-benzodioxane (12 g, 88 mmol), N-bromosuccinimide (37.6 g,211 mmol), AIBN (small amount), CCl₄ (120 ml), potassium t-butoxide (15g, 134 mmol), Et₂O (250 ml).

Yield=66% (m=12.4 g).

¹H NMR (400 MHz, CDCl₃) δ 6.05 (1H, s), 6.6-6.9 (4H, m).

Compound 56b (X=Cl)

Similary, compound 56b was prepared.

Under nitrogen, a mixture of compound 55 (5.6 g, 27.4 mmol),N-bromosuccinimide (11.7 g, 65.8 mmol) and a small amount of AIBN intetrachloromethane (340 ml) is refluxed for 5 h. After cooling, thesolid material is filtered off and the solution is evaporated to give2,3-dibromo-2,3-dihydro-1,4-benzodioxin. Under nitrogen, to a stirredsuspension of potassium t-butoxide (9.22 g, 82 mmol) in anhydroustetrahydrofuran (45 ml), was added dropwise at 0° C., a solution of2,3-dibromo-2,3-dihydro-1,4-benzodioxin in tetrahydrofuran (35 ml), andthe mixture was stirred for 4 h. The solid was filtered off on celiteand the solution is concentrated. 200 ml of water was added and theaqueous layer was extracted with dichloromethane. The organic layerswere dried over MgSO₄ and concentrated to afford a residue which waspurified by column chromatography (petroleum ether) to give 6.26 g(yield=81%) of compound 56b (white powder).

¹H NMR (400 MHz, CDCl₃) δ 6.05 (1H, s), 6.80 (1H, s), 6.85 (1H, s).

Compound 57a (X=H)

Compound 57a was prepared according to the procedure described inTetrahedron, 53(6), 1997, 2061-2074.

Reagents: compound 56a (12.4 g, 58.2 mmol), toluene (200 ml), Na₂CO₃ 2M(58 ml), phenylboronic acid (14.2 g, 116 mmol), EtOH (70 ml),tetrakis(triphenylphosphine)palladium (2.7 g, 2.3 mmol).

Yield=74% (m=9 g).

¹H NMR (400 MHz, CDCl₃) δ 6.45 (1H, s), 6.6-6.9 (4H, m), 7.25-7.5 (5H,m).

Compound 57b (X=Cl)

Similary, compound 57b was prepared.

Under nitrogen, to a solution of compound 56b (0.3 g, 1.07 mmol) in 4 mlof toluene, were added 1.1 ml of an aqueous solution o 2M Na₂CO₃,phenylboronic acid (0.26 g, 2.14 mmol) in 1.3 ml of ethanol andtetrakis(triphenylphosphine)palladium (0.05 g, 0.043 mmol). The mixturewas heated at 78° C. for 3 h.

After concentration, 30 ml of water was added and the aqueous layer wasextracted with dichloromethane. The organic layers were dried over MgSO₄and concentrated to afford a residue which was purified by columnchromatography (petroleum ether) to give 0.24 g (yield=81%) of compound57b (white powder).

¹H NMR (400 MHz, CDCl₃) δ 6.45 (1H, s), 6.80 (1H, s), 6.85 (1H, s),7.25-7.5 (5H, m).

Compound 58a (X=H)

Compound 58a was prepared according to the procedure described in Chem.of heterocyclic Compds, 35(10), 1999, 1480-1481.

Reagents: compound 57a (9 g, 42.8 mmol), phosphorus oxychloride (7.88 g,51.4 mmol), DMF (20 ml, 257 mmol).

Yield: 74% (7.5 g).

¹H NMR (400 MHz, CDCl₃) δ 6.8-7.1 (4H, m), 7.4-7.8 (5H, m), 9.15 (1H,s).

Compound 58 b (X=Cl)

Similary, compound 58b was prepared.

Under nitrogen, to a stirred solution of compound 57b (5.30 g, 19 mmol)in 120 ml of DMF was added dropwise POCl₃ (2.12 mL, 22.8 mmol). Thereaction mixture was stirred at 60° C. during 22 h. Then, the mixturewas treated with a solution of sodium acetate trihydrate (11.6 g) inwater (14 mL) and heated with stirring until crystallization began.After cooling, water was added and the precipitate was filtered off andthen washed with 2-propanol to give 4.9 g (yield=84%) of compound 58b(yellow powder).

¹H NMR (400 MHz, DMSO-d₆) δ 9.12 (1H, s), 7.75-7.52 (5H, m), 7.45 (1H,s), 7.40 (1H, s), 6.85 (1H, s).

Compound 59a (X=H)

Under nitrogen, to a stirred suspension of compound 58a (7.5 g, 31.5mmol) in 80 ml of methanol, was added at 0° C., by fraction, sodiumborohydride (0.77 g, 20.5 mmol). After 45 min, 10 ml of water was addedand the mixture was neutralized with HCl 2N and then methanol wasevaporated. After extraction with CH₂Cl₂ (2*150 ml), the organic layerwas dried over MgSO₄ and concentrated to give 7.6 g (yield=100%) ofcompound 59a (white powder).

¹H NMR (400 MHz, CDCl₃) δ 3.95 (2H, d), 5.3 (1H, t), 6.8-7.1 (4H, m),7.30-7.65 (5H, m).

Compound 59b (X=Cl)

Similary, compound 59b was prepared.

Under nitrogen at 0° C., to a stirred suspension of compound 58b (5 g,16.3 mmol) in 150 ml of methanol, was added portionwise sodiumborohydride (0.50 g, 13 mmol). After 3 h, the reaction mixture wasquenched with water (20 mL) and methanol was evaporated. The aqueousresidue was neutralized with HCl 2N and extracted with CH₂Cl₂. Theorganic layer was dried over MgSO₄, concentrated and purified by flashchromatography (petroleum ether/dichloromethane 50/50) to give 3.1 g(yield=62%) of compound 59b (white powder).

¹H NMR (400 MHz, DMSO-d₆) δ 7.57-7.43 (5H, m), 7.26 (1H, s), 7.23 (1H,s), 5.36 (1H, t), 3.96 (2H, d).

Synthesis of 3-phenylindol-2-ylmethanol 62

Compound 60: Ethyl 3-iodoindole-2-carboxylate

A 1 L round-bottom flask containing a magnetic stirring bar equippedwith a reflux condenser was charged with 10 g (0.053 mol) of ethylindole-2-carboxylate (A), 100 mL DMF, 50 mL of water, 30 g (0.106 mol)of iodine and 6.6 g (0.106 mol) of potassium hydroxide. The resultingmixture was heating at 70° C. for 3 hours. 500 mL of ice was poured intothis flask, and the mixture was agitating for an hour. After filtrationand drying, we obtained 15 g (315.1 g·mol⁻¹) of expected compound 60.

Yield: 90%.

1H NMR (400 MHz, CDCl₃) δ 1.45 (3H, t) 4.48 (2H, q) 7.22 (1H, q) 7.38(2H, m) 7.57 (1H, q) 9.23 (1H, bs).

Compound 61: Ethyl 3-phenylindole-2-carboxylate

A 250 mL round-bottom flask containing a magnetic stirring bar equippedwith a reflux condenser was charged with 4.8 g (0.0152 mol) of B, 100 mLof toluol, 1.6 g (10%) of palladium tetrakis, 50 mL of ethanol, 2.0 g(0.0167 mol) of phenylboronic acid, 50 mL of water and 5 g of potassiumcarbonate. The resulting mixture was refluxed for 48 hours. At roomtemperature, 100 mL of water was added, the mixture was extracted with2×100 mL of toluol. The organic layer was dried with magnesium sulfate,filtered and evaporated to dryness. The crude mixture was thentriturated in 20 mL of diethyl ether and filtered. We obtained 4 g(265.31 g·mol⁻¹) of the expected compound 61.

Yield: 99%.

1H NMR (400 MHz, CDCl₃) δ 1.23 (3H, t) 4.29 (2H, q) 7.15 (1H, m) 7.36(2H, m) 7.43 (2H, m) 7.45 (2H, m) 7.55 (1H, m) 7.63 (1H, m) 8.99 (1H,m).

Compound 62: 3-phenylindol-2-yl-methanol

A 250 mL round-bottom flask containing a magnetic stirring bar equippedwith a reflux condenser was charged with 1.4 g of C (0.0053 mol) and 100mL of dry THF. At room temperature, 10 mL of LiAlH₄ (1M in THF) wereadded slowly over 15 minutes. The mixture was stirring for 15 minutesand then 20 mL of crude ice was added. HCl (1M) was added until pH=1.The solution was evaporated to dryness. To the crude mixture obtainedwas added 50 mL of water. The expected product was extracted with 3×50mL of ethyl acetate. The organic layer was dried over magnesium sulfate,filtered and evaporated to dryness. The product was purified bychromatographic column with ethyl acetate as eluant. We obtained 0.8 g(223.27 g·mol⁻¹) of compound 62.

Yield: 68%.

1H NMR (400 MHz, CDCl3) δ 1.83 (1H, bs) 4.94 (2H, s) 7.14 (2H, m) 7.23(2H, m) 7.25 (1H, m) 7.38 (2H, m) 7.47 (2H, m) 7.72 (1H, m) 8.53 (1H,bs).

3) Synthesis of Compounds Ia Example 1 Compound Ia:dibenzofuran-2-ylmethylsulfanyl-acetic acid ethyl ester

To a solution of dibenzofuran (2.5 g, 14.9 mmol), ethylchloromethylthioacetate (2.5 g, 14.8 mmol) [prepared according toSynthesis, 1984, 326] in 20 mL CH₂Cl₂, SnCl₄ (1.8 ml, 15.4 mmol) wasadded at 0° C. under N₂. The reaction was concentrated after 10 minutesat 0° C. and the residue was purified by flash chromatography(cyclohexane/ethyl acetate, 5/1) to afford 2.8 g of Exemple 1 as acolorless oil.

1H NMR (400 MHz, CHCl₃) δ 1.25 (3H, t), 3.1 (2H, s), 3.9 (2H, s), 4.15(2H, q), 7.25 (1H, t), 7.4 (2H, m), 7.45 (1H, d), 7.5 (1H, d), 7.83 (1H,s), 7.87 (1H, d).

Example 2 Compound Ia: dibenzofuran-2-ylmethylsulfanyl-acetic acid

Preparation from Example 1 Scheme A Route A

Example 1 (10 g, 33.3 mmol) was dissolved in 80 mL of methanol, 80 mL ofTHF and 40 mL of H₂O, then LiOH monhydrate (3.1 g, 73.8 mmol) was added.The mixture was stirred at room temperature for 2 days. After solvantsevaporation, water was added and the resulting solution acidified to pH2. The precipitate was filtered, washed with water and dried undervacuum to afford 8.7 g of Example 2 as a white solid.

1H NMR (400 MHz, DMSO-d₆) δ 3.2 (2H, s), 4.0 (2H, s), 7.4 (1H, t), 7.47(1H, dd), 7.5 (1H, t), 8.05 (1H, s), 8.15 (1H, d).

Preparation via Scheme A Route B

Thioacetamide (30 g, 0.4 M) was added to a solution of compound 1(prepared as described earlier on) in 900 mL CHCl₃. The mixture wasrefluxed for 2 h. The resulting suspension was cooled, filtered, washedwith CH₂Cl₂, dried under vacuum to afford 33 g of compound E wherein Arcorrespond to 2-dibenzofuryl as an off-white solid.

A suspension of compound E (20.3 g, 60.4 mmol) in 23 mL 32% NaOH and 30mL water was heated at 70° C., then a solution of chloroacetic acid (6.4g, 68 mmol) in 4.5 mL 32% NaOH and 25 mL water was added to give aviscous suspension which was diluted with 50 mL water. The mixture wasrefluxed for 1 h, diluted with 500 mL of water, acidified withconcentrated HCl until pH 2. The suspension was filtered and the crudeproduct washed with water, dried under vacuum to afford 15.4 g ofExample 2 as a white solid.

1H NMR (400 MHz, DMSO-d₆) δ 3.2 (2H, s), 4.0 (2H, s), 7.4 (1H, t), 7.47(1H, dd), 7.5 (1H, t), 8.05 (1H, s), 8.15 (1H, d).

Example 3 Compound Ia: 2-(8-chlorodibenzofuran-2-yl-methylsulfanyl)acetic acid

To a solution of thiourea (3 g, 39.5 mmol) in 48% HBr (25 mL), in anheated bath (100° C.), 8-chloro-2-hydroxymethyldibenzofuran 45 (6.76 g,29 mmol) was added portionwise. The mixture was diluted with water (20mL), heated to 110° C. for 1 h 40 minutes, cooled, then filtered. Theprecipitate was washed with water, dried at 50° C. under vacuum to give10.4 g of thiouronium hydrobromide as an off-white solid. This compound(8.4 g, 22.6 mmol) was treated in 32% NaOH (20 ml) at 90° C., dilutedwith water (30 mL), then a solution of chloroacetic acid (2.5 g, 26.5mmol), NaHCO₃ (2.3 g, 27.4 mmol) in water (20 mL) was added. The mixturewas refluxed for 1 h, cooled, acidified with concentrated HCl at 5° C.The crude product was filtered, washed with water, dried under vacuum toafford 6.8 g of pure 8-chlorodibenzofuran-2-yl-methylsulfanic acid(Example J as a white solid.

1H NMR (400 MHz, CHCl₃) δ 3.13 (2H, s), 4.05 (2H, s), 7.4 (1H, dd), 7.5(3H, m), 7.91 (2H, d).

Example 4 Compound Ia: 2-(fluoren-4-ylmethylsulfanyl)acetic acid

To a solution of thiourea (4.2 g, 55.3 mmol) in 48% HBr (25 ml) heatedin a bath of 80° C., was added Compound 13 (9 g, 45.9 mmol) to give athick suspension which was diluted with 15 ml of water. The resultantmixture was refluxed for 10 minutes, then cooled, filtered, washed withwater to give a beige solid.

A mixture of above obtained compound in 16% NaOH (40 ml) was heated at70° C., then a solution of chloroacetic acid (5 g, 52.9 mmol) in 1N NaOH(50 ml) was added. The resulting mixture was heated at reflux for 90minutes, filtered while hot, the filtrate was cooled and acidified byconcentrated HCl to pH 2 to give a suspension that was filtered, washedby water, dried in vacuum to afford 9 g of pure Example 4 as a brownishsolid.

1H NMR (400 MHz, DMSO-d₆) δ: 3.25 (2H, s), 3.97 (2H, s), 4.25 (2H, s),7.25 (2H, m), 7.33 (1H, t), 7.43 (1H, t), 7.53 (1H, d), 7.6 (1H, d), 8.0(1H, d).

Example 5 Compound Ia: 2-(2-dibenzothiophen-methylsulfanyl)acetic acid

To a solution of thiourea (4.7 g, 61.8 mmol) in 48% HBr (30 ml) heatedin a bath of 80° C., was added Compound 19 (10.7 g, 50 mmol) to give avery thick suspension which was diluted with 30 ml of 48% HBr and 20 mlwater. The resultant mixture was refluxed for 2 hr, then cooled,filtered, washed with water, dried to give 17.3 of white solid.

The above obtained compound was mixed with 32% NaOH (25 ml) and 20 mlwater, heated at 70° C., then a solution of sodium chloroacetate (6 g,51.5 mmol) in water (50 ml) was added to give a solution. The resultingmixture was heated at reflux for 60 minutes, cooled, diluted by water(200 ml) and acidified by concentrated HCl to pH 2 to give a suspensionthat was extracted by methylenechloride, the organic phase was washed bybrine, dried over Na₂SO₄, evaporated to afford 13 g of pure Example 5 asa yellowish solid.

1H NMR (400 MHz, DMSO-d₆) δ: 3.2 (2H, s), 4.0 (2H, s), 7.5 (3H, m), 8.0(1H, d), 8.03 (1H, m), 8.28 (1H, s), 8.33 (1H, m).

Example 6 Compound Ia:2-(8-fluorodibenzofuran-2-yl-methylsulfanyl)acetic acid

To a solution of thiourea (3.7 g, 48.7 mmol) in 48% HBr (45 ml) heatedin a bath of 80° C., was added 8-fluoro-2-hydroxymethyldibenzofuran 44(8.4 g, 38.9 mmol) to give a very thick suspension which was dilutedwith 15 ml water. The resultant mixture was refluxed for 2 hr, thencooled, filtered, washed with water, dried to give a white solid.

The above obtained compound was mixed with 32% NaOH (20 ml), heated at70° C., then a solution of sodium chloroacetate (4.7 g, 40.3 mmol) inwater (40 ml) was added to give a suspension. The resulting mixture washeated at reflux for 60 minutes, cooled, diluted by water (500 ml) andacidified by concentrated HCl to pH 2 to give a suspension that wasfiltered, rinsed with water dried in vacuum to afford 11 g of pureExample 6 as a beige solid.

1H NMR (400 MHz, DMSO-d₆) δ: 3.18 (2H, s), 4.0 (2H, s), 7.35 (1H, dt),7.5 (1H, d), 7.66 (1H, d), 7.75 (1H, dd), 8.0 (1H, d), 8.03 (1H, dd),8.1 (1H, s).

Example 7 Compound Ia:(3-phenyl-benzo[b]thiophen-2-ylmethylsulfanyl)-acetic acid

To a mixture of thiourea (2.74 g, 36 mmol) and 48% HBr (15.75 mL) inwater (3 mL) at 60° C., compound 3 (7.2 g, 30 mmol) was added in oneportion was added. The reaction mixture was then gently heated to refluxfor 5 mm, cooled. The mixture of HBr and water was decanted from theresulting oil, water was added and decanted again. To the resultingresidue, aqueous NaOH (10N, 12 mL) was added, and the mixture heated to70° C. A solution of sodium chloroacetate (33 mmol) in 9 mL of water wasslowly added. The reaction mixture was then heated to 110° C. for 1 h,cooled, diluted with ice-water (100 mL), and acidified with conc.hydrochloric acid (pH-2). The resulting acidic mixture was extractedinto diethyl ether (2×150 mL), the separated organic layer was washedwith a solution of NaOH (4 N) and the aqueous layer acidified again(pH-2), extracted into diethyl ether (400 mL). The combined organiclayers were dried over Na₂SO₄, and solvent evaporated to generate 7 g ofcompound 50 as a yellow oil.

Yield=74%,

R_(f)=0.4 (eluent: CH₂Cl₂/CH₃OH 9/1).

In the following examples 8 to 10 compound Ia from example 2, 5 and 6where R═H were converted into their corresponding compound Ia whereR═CH₃ (methyl ester).

Example 8 Compound Ia: 2-(dibenzofuran-2-ylmethylsulfanyl)acetic acidmethyl ester

A mixture of the Example 2 (4.22 g, 15.5 mmol) in methanol (30 ml) andconcentrated H₂SO₄ (1 ml) was refluxed for 2 hr and then evaporated. Theresidue was dissolved in 100 ml methylenechloride, washed by water,dried over Na₂SO₄, purified by flash chromatography (cyclohexane/ethylacetate, 5/1) to furnish 3.7 g of Example 8 as a yellowish oil.

HPLC: Ret. Time=15.92 min (Column: Zorbax Eclipse XDB-C8; 4.6*150 mm, 5μm; Mobile Phase: A: 0.1% TFA in H₂O, B: 0.1% TFA in ACN; Gradient:10-100% B in 20 min.; Flow Rate: 1 ml/min.; Temperature: 25° C.)

1H NMR (400 MHz, CHCl₃) δ 3.1 (2H, s), 3.75 (3H, s), 3.9 (2H, s), 7.25(1H, t), 7.4 (2H, m), 7.45 (1H, d), 7.5 (1H, d), 7.83 (1H, s), 7.87 (1H,d).

Example 9 Compound Ia: 2-(dibenzothiophen-2-ylmethylsulfanyl) aceticacid methyl ester

A mixture of the Example 5 (2.88 g, 10 mmol) in methanol (30 ml) andconcentrated H₂SO₄ (1 ml) was heated at reflux for 2 hr, thenevaporated, the residue was dissolved in 100 ml methylenechloride,washed by water, dried over Na₂SO₄, purified by flash chromatography(cyclohexane/ethyl acetate, 5/1) to furnish 2.72 g of Example 2 as ayellowish oil.

1H NMR (400 MHz, CHCl₃) δ 3.11 (2H, s), 3.75 (3H, s), 4.3 (2H, s), 7.5(3H, m), 7.81 (1H, d), 7.84 (1H, m), 8.13 (1H, s), 8.18 (1H, m).

Example 10 Compound Ia: 2-(8-fluorodibenzofuran-2-ylmethylsulfanyl)acetic acid methyl ester

A mixture of the Example 6 (2.9 g, 10 mmol) in methanol (30 ml) andconcentrated H₂SO₄ (1 ml) was heated at reflux for 2 hr, thenevaporated, the residue was dissolved in 100 ml methylenechloride,washed by water, dried over Na₂SO₄, purified by flash chromatography(cyclohexane/ethyl acetate, 5/1) to furnish 2.34 g of Example 10 as acolorless oil.

1H NMR (400 MHz, CHCl₃) δ 3.11 (2H, s), 3.75 (3H, s), 4.3 (2H, s), 7.5(3H, m), 7.81 (1H, d), 7.84 (1H, m), 8.13 (1H, s), 8.18 (1H, m).

Example 11 Compound Ia: 2-(8-methoxydibenzofuran-2-ylmethylsulfanyl)acetic acid ethyl ester

(Synthesis: Route D)

To a solution of compound 46 (5.48 g, 24 mmol) in methylenechloride (120ml), were added at RT ethyl thioglycolate (3.1 g, 25.8 mmol) and ZnI₂(8.5 g, 26.6 mmol) to give a suspension. The reaction was stirred at RTfor 2 hr, quenched by water, the organic phase was dried over Na₂SO₄,evaporated, the residue was purified by flash chromatography(cyclohexane/ethyl acetate, 6/1) to furnish 3.58 g of Example 11 as acolorless oil.

HPLC: Ret. Time=16.66 min (the same conditions as described for Example8)

Example 12 Compound Ia: 2-(2-benzofuran-2-yl-benzylsulfanyl) acetic acidethyl ester

To a solution of compound 7 (3.18 g, 14.2 mmol) in methylenechloride (30ml), were added at RT ethyl thioglycolate (1.75 g, 14.6 mmol) and ZnI₂(4.7 g, 14.7 mmol) to give a suspension. The reaction was stirred at RTfor 1 hr, quenched by water, the organic phase was dried over Na₂SO₄,evaporated, the residue was purified by flash chromatography(cyclohexane/ethyl acetate, 8/1) to furnish 3 g of Example 12 as acolorless oil.

1H NMR (400 MHz, CHCl₃) δ 1.25 (3H, t), 3.25 (2H, s), 4.13 (2H, q), 4.25(2H, s), 7.3 (2H, m), 7.4 (1H, t), 7.5 (3H, t), 7.75 (1H, d), 7.86 (2H,d).

Example 13

Compound Ia: wherein Ar is 3-phenyl-1,4 benzodioxin, Y is CH₂, q is 0,substitution in position 2 and R¹ is COOCH₃.

To a solution of (3-phenyl-1,4-benzodioxin-2-yl)methanol (compound C,7.60 g, 31.6 mmol) in dichloroethane (200 mL) under N₂, was addedsuccessively methyl thioglycolate (3.35 g, 31.6 mmol) and ZnI₂ (10.08 g,31.6 mmol). The mixture was stirred at room temperature for 2 h30 andthen 60 mL of water was added. After decantation, the aqueous layer wasextracted with dichloromethane (100 mL). The organic layers were driedover MgSO₄ and concentrated to furnish 10.2 g of Example 13 (yellowoil).

Yield=98%,

¹H-NMR (400 MHz, CDCl₃): δ 3.35 (2H, s), 3.47 (2H, s), 3.59 (3H, s),6.7-6.9 (4H, m), 7.3-7.6 (5H, m).

4) Synthesis of Compounds Ib Example 14 Compound Ib:2-(dibenzofuran-2-ylmethylsulfinyl)acetic acid

To a solution of Exemple 2 (13.6 g, 50 mmol) in acetic acid (130 mL),was added 30% H₂O₂ (8 mL, 79 mmol). The mixture was stirred at roomtemperature for 3 h. the obtained suspension was filtered, washed withacetic acid (50 mL) and methanol (50 mL), dried under vacuum to afford12.5 g of Example 14 as a white solid.

1H NMR (400 MHz, DMSO-d₆) δ 3.6 (1H, d), 3.9 (1H, d), 4.25 (1H, d), 4.45(1H, d), 7.45 (1H, t), 7.5 (1H, d), 7.65 (1H, t), 7.75 (2H, m), 8.1 (1H,s), 8.2 (1H, d).

5) Synthesis of Compounds Ic Example 15

Compound Ic wherein Ar is dibenzofuran-2-yl, Y is CH₂, q is 0,NR¹²R¹³=4-(2-hydroxyethyl)piperazin-1-yl.

To a mixture of Example 2 (0.5 g, 1.8 mmol),N-(2-hydroxyethyl)piperazine (0.25 g, 1.9 mmol), HOBt (0.25 g, 18.5mmol) in 50 ml methylenechloride was added EDCI (0.46 g, 2.4 mmol) atRT. The reaction was maintained for 16 h, then washed with water, driedover MgSO₄, evaporated, the residue was chromatographied(methylenechloride/methanol, 10/1) to furnish 0.5 g of Example 16 as acolorless oil which crystallized on stand.

1H NMR (400 MHz, CHCl₃) δ 2.5 (6H, m), 3.2 (2H, s), 3.45 (2H, m), 3.65(4H, m), 4.0 (2H, s), 7.35 (1H, t), 7.5 (4H, m), 7.95 (1H, d), 7.98 (1H,s).

Example 16 Compound Ic: 2-(dibenzofuran-2-ylmethylsulfanyl)acetamide

A mixture of Exemple 8 (3.7 g, 12.9 mmol) in methanol (100 ml) and 28%aqueous ammonia (50 ml) was stirred at RT for 16 hr to give a suspensionthat was filtered, washed by water, dried in vacuum to furnish 2.7 g ofExample 16 as a white solid.

1H NMR (400 MHz, DMSO-d₆) δ 3.04 (2H, s), 4 (2H, s), 7.03 (1H, bs), 7.6(4H, m), 7.7 (2H, dd), 8.08 (1H, s), 8.13 (1H, d).

Example 17 Compound Ic:2-(8-methoxy-dibenzofuran-2-ylmethylsulfanyl)acetamide

A mixture of Example 11 (1.1 g, 3.3 mmol) in ethanol (20 ml) and 28%aqueous ammonia (30 ml) was stirred at RT for 18 hr to give a suspensionthat was filtered, washed by water, dried in vacuum to furnish 0.71 g ofexample 17 as a white solid.

HPLC: Ret. Time=11.68 min. (the same conditions as described for Example8)

Example 18 Compound Ic: 2-(dibenzothiophen-2-ylmethylsulfanyl)acetamide

A mixture of Example 2 (2.72 g, 9 mmol) in methanol (50 ml) and 28%aqueous ammonia (30 ml) was stirred at room temperature for 16 hr togive a suspension. After evaporation of methanol, the aqueous residuewas filtered, washed by water, dried in vacuum to furnish 2.1 g ofExample 18 as a white solid.

1H NMR (400 MHz, DMSO-d₆) δ 3.04 (2H, s), 4 (2H, s), 7.03 (1H, bs), 7.5(4H, m), 7.91 (2H, d), 8.02 (1H, m), 8.3 (1H, s), 8.33 (1H, m).

Example 19 Compound Ic:2-(8-fluorodibenzofuran-2-ylmethylsulfanyl)acetamide

A mixture of Example 10 (2.34 g, 7.7 mmol) in methanol (50 ml) and 28%aqueous ammonia (30 ml) was stirred at room temperature for 16 hr togive a suspension. The methanol was evaporated and the aqueous residuewas filtered, washed by water, dried in vacuum to furnish 1.68 g ofExample 19 as a white solid.

1H NMR (400 MHz, DMSO-d₆) δ 3.04 (2H, s), 4 (2H, s), 7.03 (1H, bs), 7.35(1H, dt), 7.43 (1H, bs), 7.5 (1H, d), 7.67 (1H, d), 7.75 (1H, dd), 8.01(1H, dd), 8.1 (1H, s).

Example 20 Compound Ic:2-(2-benzofuran-2-yl-benzylsulfanyl)-N,N-dimethyl acetamide

To a mixture of Example 12 (1.12 g, 3.43 mmol) and dimethylaminehydrochloride (0.3 g, 3.68 mmol) in methylenechloride (20 ml) was addedat RT a 2 N solution of Al(CH₃)₃ in toluene (2 ml, 4 mmol). Theresulting mixture was stirred at RT for 24 hr, then quenched by 0.1 NHCl (20 ml), the organic phase was washed by water, dried over MgSO₄,purified by flash chromatography (Methylenechloride/methanol, 40/1) tofurnish 1 g of Example 20 as a yellowish oil.

1H NMR (400 MHz, CHCl₃) δ 2.95 (6H, d), 3.4 (2H, s), 4.25 (2H, s), 4.7(1H, d), 7.3 (2H, m), 7.4 (1H, t), 7.5 (3H, t), 7.75 (1H, dd), 7.88 (2H,d).

Example 21 Compound Ic:2-(8-chlorodibenzofuran-2-yl-methylsulfanyl)-1-[4-(2-hydroxyethyl)piperazin-1-yl]ethanone

To a mixture of Example 3 (1.48 g, 4.8 mmol),4-(2-hydroxyethyl)-piperazine (0.65 g, 5 mmol) and HOBt (0.65 g, 4.8mmol) in methylenechloride (50 ml), was added EDCI (1.2 g, 6.25 mmol) atRT. The reaction was maintained at RT for 16 hr, quenched by water, theorganic phase was washed by water, dried over Na₂SO₄, evaporated to give1.92 g of pure Example 21.

HPLC: Ret. Time=10.7 min. (the same conditions as described for Example8)

Example 22 Compound Ic:4-[2-(8-chlorodibenzofuran-2-yl-methylsulfanyl)acetyl]-piperazine-1-carboxylicacid tret-butyl ester

To a mixture of Example 3 (2 g, 6.5 mmol),4-(tert-butoxycarbonyl)-piperazine (1.3 g, 7 mmol) and HOBt (1.2 g, 8.9mmol) in methylenechloride (50 ml), was added EDCI (1.7 g, 8.9 mmol) atRT. The reaction was maintained at RT for 1.5 hr, quenched by water, theorganic phase was washed by water, dried over Na₂SO₄, evaporated, theresidue was purified by flash chromatography(Methylenechloride/methanol, 40/1) to give 2.75 g of Example 22 as awhite solid.

1H NMR (400 MHz, CHCl₃) δ 1.5 (9H, s), 3.25 (2H, s), 3.45 (6H, m), 3.59(2H, m), 4.0 (2H, s), 7.4 (1H, dd), 7.5 (3H, m), 7.96 (2H, d).

Example 23 Compound Ic:1-(4-acetyl-piperazin-1-yl)-2-(8-chlorodibenzofuran-2-yl-methylsulfanyl)-ethanone

To a mixture of acid Example 3 (1.83 g, 6 mmol), 4-(acetyl)-piperazine(0.8 g, 6.3 mmol) and HOBt (1 g, 4.8 mmol) in methylenechloride (50 ml),was added EDCI (1.5 g, 7.8 mmol) at RT. The reaction was maintained atRT for 5 hr, quenched by water, the organic phase was washed by water,dried over Na₂SO₄, evaporated, the residue was purified by flashchromatography (methylenechloride/methanol, 30/1) to give 2.14 g ofExample 23.

HPLC: Ret. Time=12.81 min. (the same conditions as described for Example8)

Example 24 Compound Ic:2-(9H-fluoren-4-ylmethylsulfanyl)-1-[4-(2-hydroxyethyl)-piperazin-1-yl]-ethanone

To a mixture of acid Example 4 (6 g, 22.2 mmol),4-(2-hydroxyethyl)-piperazine (3 g, 23 mmol) and HOBt (2.5 g, 18.5 mmol)in methylenechloride (200 ml), was added EDCI (4.6 g, 24 mmol) at RT.The reaction was maintained at RT for 2 hr, quenched by water, theorganic phase was washed by water, dried over Na₂SO₄, evaporated, theresidue was purified by flash chromatography(methylenechloride/methanol, 10/1) to give 6.26 g of Example 24.

1H NMR (400 MHz, CHCl₃) δ 2.43 (2H, m), 2.5 (4H, m), 3.3 (2H, s), 3.38(2H, t), 3.63 (4H, m), 3.58 (2H, s), 3.97 (2H, s), 4.28 (2H, s), 7.25(1H, m), 7.33 (2H, m), 7.41 (1H, t), 7.48 (1H, d), 7.57 (1H, d), 7.88(1H, d).

Example 25 Compound Ic:4-[2-(dibenzothiophen-2-ylmethylsulfanyl)-acetyl]-piperazine-1-carboxylicacid tert-butyl ester

To a mixture of acid Example 5 (5.76 g, 20 mmol),4-(tert-butoxycarbonyl)-piperazine (3.75 g, 20.2 mmol) and HOBt (3.4 g,25 mmol) in methylenechloride (150 ml), was added EDCI (4.8 g, 25 mmol)at RT. The reaction was maintained at RT for 3 hr, quenched by water,the organic phase was washed by 0.5 N HCl, water, dried over Na₂SO₄,evaporated, the residue was purified by flash chromatography(cyclohexane/ethyl acetate, 3/4) to give 8.3 g of Example 25 as a whitesolid.

1H NMR (400 MHz, CHCl₃) δ 1.5 (9H, s), 3.25 (2H, s), 3.45 (6H, m), 3.59(2H, m), 4.0 (2H, s), 7.45 (3H, m), 7.8 (1H, d), 7.87 (1H, m), 8.16 (1H,s), 8.19 (1H, m).

Example 26 Compound Ic:4-[2-(8-fluorodibenzofuran-2-yl-methylsulfanyl)acetyl]-piperazine-1-carboxylicacid tret-butyl ester

To a mixture of acid Example 6 (5.8 g, 20 mmol),4-(tert-butoxycarbonyl)-piperazine (3.72 g, 20 mmol) and HOBt (3.4 g, 25mmol) in methylenechloride (150 ml), was added EDCI (4.8 g, 25 mmol) atRT. The reaction was maintained at RT for 1 hr, quenched by water, theorganic phase was washed by 0.5 N HCl, water, dried over Na₂SO₄,evaporated to give a beige solid which was recrystallized in ethylacetate (30 ml) to give 6.46 g of Example 26 as a beige solid.

1H NMR (400 MHz, CHCl₃) δ 1.5 (9H, s), 3.25 (2H, s), 3.45 (6H, m), 3.59(2H, m), 4.0 (2H, s), 7.18 (1H, dt), 7.45 (3H, m), 7.61 (1H, dd), 7.92(1H, s).

Example 27 Compound Ic:2-(3-phenyl-benzo[b]thiophen-2-ylmethylsulfanyl)-1-pyrrolidin-1-yl-ethanone

To a cooled (ice-bath) solution of Example 7 (2.14 g, 6.8 mmol) inCH₂Cl₂ (40 mL), was added successively pyrrolidine (0.63 mL, 7.5 mmol),EDCI (1.44 g, 7.5 mmol) and HOBT (1.012 g, 7.5 mmol). The cooling bathwas removed and the mixture was stirred at room temperature for onenight, diluted with CH₂Cl₂ (50 mL), washed successively with water (50mL), aqueous Na₂CO₃ (50 mL) water (30 mL) and dried over Na₂SO₄. Onconcentration, the solution generated a crude product that was purifiedby column chromatography (CH₂Cl₂/CH₃OH 9.6/0.4) to give 1.76 g ofExample 27 (orange oil).

Yield=70%,

R_(f)=0.8 (eluent: CH₂Cl₂/CH₃OH 9/1).

The following examples were prepared according to the process asdescribed for Example 27:

Example 28 Compound Ic:N,N-dimethyl-2-(3-phenyl-benzo[b]thiophen-2-ylmethylsulfanyl)-acetamide.

Reagents: Example 7 (2.14 g, 6.8 mmol) in CH₂Cl₂ (40 mL), 40% aqueousdimethylamine (0.337 g, 0.85 mL, 7.5 mmol), EDCI (1.44 g, 7.5 mmol) andHOBT (1.012 g, 7.5 mmol).

Example 28 as a yellow orange oil was directly used in the next stepwithout any further purification.

Yield=96%,

R_(f)=0.6 (eluent: CH₂Cl₂/CH₃OH 9.5/0.5).

Example 29 Compound Ic:N-isopropyl-2-(3-phenyl-benzo[b]thiophen-2-ylmethylsulfanyl)-acetamide

Reagents: Example 7 (2.14 g, 6.8 mmol) in CH₂Cl₂ (40 mL), isopropylamine(0.44 g, 0.65 mL, 7.5 mmol), EDCI (1.44 g, 7.5 mmol) and HOBT (1.012 g,7.5 mmol).

The crude product was crystallized in diisopropyl oxyde to give 0.62 gof Example 29 (white powder)

Yield=26%.

Rf (CH₂Cl₂/CH₃OH 9/1)=0.8

Example 30 Compound Ic:1-(4-hydroxy-piperidin-1-yl)-2-(3-phenyl-benzo[b]thiophen-2ylmethylsulfanyl)-ethanone

Reagents: Example 7 (2.198 g, 7 mmol) in CH₂Cl₂ (40 mL),N-hydroxypiperidine (0.788 g, 7.7 mmol), EDCI (1.474 g, 7.7 mmol) andHOBT (1.039 g, 7.7 mmol).

Yield=39.5%, 1.1 g of Example 30 as a yellow oil.

Rf (CH₂Cl₂/CH₃OH 9/1)=0.5.

Example 31 Compound Ic:1-(4-acetyl-piperazin-1-yl)-2-(3-phenyl-benzo[b]thiophen-2-ylmethylsulfanyl)-ethanone

Reagents: Example 7 (3.01 g, 9.6 mmol) in CH₂Cl₂ (58 mL),N-acetylpiperazine (1.39 g, 10.86 mmol), EDCI (2.02 g, 10.86 mmol) andHOBT (1.46 g, 10.86 mmol).

The crude product that was purified by column chromatography(CH₂Cl₂/CH₃OH 9.5/0.5) to give 1.38 g of Example 31 (yellow oil)

Yield=34.5,

Rf (CH₂Cl₂/CH₃OH 9.5/0.5)=0.2.

Example 32 Compound IcN-(2-hydroxy-ethyl)-2-(3-phenyl-benzo[b]thiophen-2-ylmethylsulfanyl)-acetamide

Reagents: Example 7 (2.36 g, 7.51 mmol) in CH₂Cl₂ (40 mL), ethanolamine(0.506 g, 8.3 mmol), EDCI (1.59 g, 8.3 mmol) and HOBT (1.12 g, 8.3mmol).

The crude product that was purified by column chromatography(CH₂Cl₂/CH₃OH 9.4/0.6) to give 0.72 g of Example 32 as a solid.

Yield=27%.

Rf (CH₂Cl₂/CH₃OH 9/1)=0.8

Example 33 Compound Ic:1-[4-(3-Phenyl-benzo[1,4]dioxin-2-ylmethylsulfanylmethyl)-piperazin-1-yl]-ethanone

Under N₂, to a solution of Example 13 (1.5 g, 4.57 mmol) indichloromethane (20 mL), were added successively N-acetylpiperazine(0.70 g, 5.48 mmol) in one portion and AlMe₃ 2N in toluene (2.74 mL)dropwise. The mixture was stirred at room temperature for one night andthen refluxed for 3 h. After cooling, few mL of water was added slowly.After decantation, the organic layer was dried over MgSO₄ andconcentrated to afford the crude product which was purified by columnchromatography (CH₂Cl₂/MeOH 98/2) to give 0.78 g (yield=40%) of Example33 (yellow oil).

¹H-NMR (400 MHz, CDCl₃): δ 2.11 (3H, d), 3.3-3.7 (12H, m), 6.6-6.9 (4H,m), 7.3-7.6 (5H, m).

6) Synthesis of Compounds Id Example 34 Compound Id:4-[2-(dibenzofuran-2-ylmethylsulfinyl)-acetyl]-piperazine-1-carboxylicacid ethyl ester

To a mixture of Exemple 14 (4.32 g, 15 mmol),N-(ethoxycarbony)piperazine (2.5 g, 15.8 mmol) and HOBt (2 g, 15 mmol)in 150 ml methylenechloride, was added EDCI (3.6 g, 18.8 mmol) at RT.The reaction was maintained for 2 h, then washed with 0.5 N HCl (100 ml)and water, dried over Na₂SO₄, evaporated to a white solid that wasrecrystallized in 15 ml ethyl acetate to afford 3.6 g of Example 34 as awhite solid; additional 0.85 g of Example 34 were obtained from thefiltrate by flash chromatography (methylenechloride/methanol, 10/1).

1H NMR (400 MHz, DMSO-d₆) δ 1.2 (3H, t), 3.35 (4H, m), 3.5 (4H, m), 4.0(4H, m), 4.2 (1H, d), 4.45 (1H, d), 7.45 (1H, t), 7.5 (1H, d), 7.6 (1H,t), 7.75 (2H, dd), 8.1 (1H, s), 8.2 (1H, d).

MS:M+H=429, M+Na=451, M+K=467

7) Synthesis of Compounds Id Example 35 Compound Id:2-(dibenzofuran-2-ylmethylsulfinyl)-1-[4-(2-hydroxyethyl)-piperazin-1-yl]-ethanone

To a solution of Example 15 (0.5 g, 1.3 mmol) in 20 ml acetic acid, wasadded 30% H₂O₂ (0.2 ml, 2 mmol) was added. The oxidation was maintainedat RT for 18 h, then evaporated, the residue was purified by flashchromatography (methylenechloride/methanol, 9/1) to afford 0.39 g ofExample 34 as a white solid.

1H NMR (400 MHz, CHCl₃) δ 2.5 (6H, m), 3.4 (2H, m), 3.65 (6H, m), 4.25(1H, d), 4.5 (1H, d), 7.33 (1H, t), 7.5 (2H, m), 7.6 (1H, d), 7.92 (1H,d), 7.98 (1H, s).

MS:MS:M+H=401, M+Na=423

Example 36 Compound Id: 2-(dibenzofuran-2-ylmethylsulfinyl)acetamide

A mixture of Exemple 16 (2.7 g, 10 mmol) in acetic acid (40 ml) and 30%H₂O₂ (1.6 ml) was stirred at RT for 1.5 hr to give a solution that wasevaporated to give white solid. The crystallization in ethanol (30 ml)furnished 2.6 g of Example 36 as a white solid.

1H NMR (400 MHz, DMSO-d₆) δ 3.43 (1H, d), 3.68 (1H, d), 4.17 (1H, d),4.43 (1H, d), 7.33 (1H, bs), 7.43 (1H, t), 7.47 (1H, d), 7.54 (1H, t),7.68 (1H, bs), 7.73 (2H, m), 8.07 (1H, s), 8.17 (1H, d).

MS:M+Na=310

Example 37 Compound Id:2-(8-methoxydibenzofuran-2-ylmethylsulfinyl)acetamide

A mixture of Example 17 (0.71 g, 2.36 mmol) in acetic acid (20 ml) and30% H₂O₂ (0.45 ml) was stirred at RT for 1 hr to give a solution thatwas evaporated to give an oil. The crystallization in ethanol furnished0.48 g of Example 37 as a white solid.

1H NMR (400 MHz, DMSO-d₆) δ 3.46 (1H, d), 3.69 (1H, d), 3.87 (3H, s),4.17 (1H, d), 4.41 (1H, d), 7.1 (1H, dd), 7.33 (1H, bs), 7.46 (1H, d),7.59 (1H, d), 7.69 (3H, m), 8.06 (1H, s).

MS:M+Na=340

Example 38 Compound Id:2-(8-fluorodibenzofuran-2-ylmethylsulfinyl)acetamide

A mixture of Example 19 (1.68 g, 5.8 mmol) in acetic acid (30 ml) and30% H₂O₂ (0.9 ml) was stirred at RT for 3 hr to give a solution that wasevaporated to give an oil. The crystallization in ethanol (30 ml)furnished 1.36 g of Example 38 as a white powder.

1H NMR (400 MHz, DMSO-d₆) δ 3.46 (1H, d), 3.69 (1H, d), 4.18 (1H, d),4.43 (1H, d), 7.38 (2H, m), 7.53 (1H, d), 7.75 (3H, m), 8.03 (2H, m),8.1 (1H, s).

MS:M+Na=328

Example 39 Compound Id: 2-(dibenzothiophen-2-ylmethylsulfinyl)acetamide

A mixture of Example 18 (2.1 g, 7.3 mmol) in acetic acid (40 ml) and 30%H₂O₂ (1.1 ml) was stirred at RT for 2.5 hr to give a solution that wasevaporated to give an oil. The crystallization in ethanol (50 ml)furnished 1.45 g of Example 39 as a beige solid.

1H NMR (400 MHz, DMSO-d₆) δ 3.5 (1H, d), 3.75 (1H, d), 4.2 (1H, d), 4.48(1H, d), 7.36 (1H, bs), 7.5 (1H, d), 7.54 (2H, m), 7.75 (1H, bs), 8.03(2H, d), 8.28 (1H, s), 8.33 (1H, m).

MS:M+Na=326

Example 40 Compound Id:2-(8-chlorodibenzofuran-2-yl-methanesulfinyl)-[4-(2-hydroxyethyl)piperazin-1-yl]ethanone

A mixture of Example 21 (1.92 g, 4.6 mmol) in acetic acid (40 ml) and30% H₂O₂ (0.85 ml) was stirred at RT for 2 hr, then evaporated to give asolid which was dissolved in methylenehloride (100 ml) and water (50ml). The mixture was alkalized to pH 10 by 1 N NaOH. The organic phasewas washed by water, dried over Na₂SO₄, purified by flash chromatography(methylenechloride/methanol, 9/1) to give 1.2 g Example 40 as a whitesolid.

1H NMR (400 MHz, CDCl₃) δ 2.5 (6H, m), 3.47 (2H, m), 3.66 (5H, m), 3.74(1H, m), 4.25 (1H, d), 4.5 (1H, d), 7.43 (1H, dd), 7.5 (2H, m), 7.58(1H, d), 7.92 (2H, d).

MS:M+H=435, M+Na=457

Example 41 Compound Id:2-(8-chlorodibenzofuran-2-yl-methanesulfinyl)-1-piperazin-1-ylethanone

A mixture of Example 22 (2.67 g, 5.6 mmol) in methylenechloride (15 ml)and trifluoroacetic acid (7 ml) was stirred at RT for 0.5 h, thenevaporated to dryness. The residue was dissolved in 20 ml water and 20ml methylenechloride, then neutralized to pH 8 by NaHCO₃ powder, theorganic phase was washed by water, dried over Na₂SO₄, evaporated to givethe deprotected intermediate which was mixed with acetic acid (40 ml)and 30% H₂O₂ (1 ml). The mixture was stirred at RT for 2 hr, evaporated,purified by flash chromatography (methylenechloride/methanol, 10/1saturated by 28% aqueous ammonia) followed by crystallization in 10 mlethyl acetate to give 1.95 g Example 41 as a white solid.

1H NMR (400 MHz, DMSO-d₆) δ 2.5 (4H, m), 3.25 (4H, m), 3.87 (2H, dd),4.07 (1H, d), 4.31 (1H, d), 7.43 (2H, m), 7.63 (2H, dd), 8.0 (1H, s),8.2 (1H, s).

MS:M+H=391, M+Na=413

Example 42 Compound Id:1-(4-acetylpiperazin-1-yl)-2-(8-chlorodibenzofuran-2-yl-methanesulfinyl)-ethanone

A mixture of Example 23 (2.1 g, 5 mmol) in acetic acid (30 ml) and 30%H₂O₂ (0.8 ml) was stirred at RT for 2 hr, then diluted with 300 ml waterto give a suspension that was heated to give a solution, cooled,filtered, rinsed with water, dried in vacuum to give 1.78 g Example 42as a white solid.

1H NMR (400 MHz, CDCl₃) δ 2.16 (3H, d), 3.4-3.83 (10H, m), 4.25 (1H,dd), 4.5 (1H, dd), 7.43 (1H, dd), 7.5 (2H, m), 7.59 (1H, d), 7.91 (1H,s), 7.96 (1H, d).

MS:M+H=433, M+Na=455

Example 43 Compound Id:2-(9H-fluoren-4-ylmethanesulfinyl)-1-[4-(2-hydroxyethyl)piperazin-1-yl]-ethanone

A mixture of Example 24 (2.9 g, 7.6 mmol) in acetic acid (40 ml) and 30%H₂O₂ (1.2 ml) was stirred at RT for 3 hr, then evaporated. The residuewas dissolved in 50 ml water and neutralized at pH 7 by K₂CO₃ powder togive a solution that was extracted methylenechloride (3*50 ml). Theextracts were washed by brine, dried over Na₂SO₄, evaporated. Flashchromatography (methylenechloride/methanol, 9/1) followed byrecrystallization in ethyl acetate/methylenechloride (10/1) afforded 2 gExample 43 as a white crystal.

1H NMR (400 MHz, CDCl₃) δ 2.5 (7H, m), 3.43 (2H, m), 3.61 (4H, m), 3.69(1H, d), 3.86 (1H, d), 3.92 (2H, s), 4.61 (1H, d), 4.91 (1H, d), 7.3(2H, m), 7.4 (2H, m), 7.56 (2H, m), 8.0 (1H, d).

MS:M+H=399, M+Na=421, M+K=437

Example 44 Compound Id:2-(dibenzothiophen-2-yl-methanesulfinyl)-1-piperazin-1-yl-ethanone

A mixture of Example 25 (2 g, 4.4 mmol) in methylenechloride (20 ml) andtrifluoroacetic acid (8 ml) was stirred at RT for 0.5 h, then evaporatedto dryness. The residue was dissolved in 50 ml water and 20 mlmethylenechloride, then neutralized to pH 8 by 0.5 N NaOH, the organicphase was washed by water, dried over Na₂SO₄, evaporated to give thedeprotected intermediate which was mixed with acetic acid (30 ml) and30% H₂O₂ (0.8 ml). The mixture was stirred at RT for 1.5 hr, evaporated,purified by flash chromatography (methylenechloride/methanol, 10/1saturated by 28% aqueous ammonia) to give 0.6 g Example 44 as a whitesolid.

1H NMR (400 MHz, CDCl₃) δ 2.81 (2H, m), 2.87 (2H, m), 3.36 (2H, m), 3.63(4H, m), 4.28 (1H, d), 4.5 (1H, d), 7.46 (3H, m), 7.86 (2H, m), 8.17(2H, m).

MS:M+H=373, M+Na=395

Example 45 Compound Id:2-(8-fluorodibenzofuran-2-yl-methanesulfinyl)-1-piperazin-1-ylethanone

A mixture of Example 26 (6.4 g, 14 mmol) in methylenechloride (40 ml)and trifluoroacetic acid (20 ml) was stirred at RT for 0.5 h, thenevaporated to dryness. The residue was dissolved in 100 ml water and 100ml methylenechloride, then neutralized to pH 8 by 0.5 N NaOH, theorganic phase was washed by water, dried over Na₂SO₄, evaporated to givethe deprotected intermediate which was mixed with acetic acid (100 ml)and 30% H₂O₂ (2.5 ml). The mixture was stirred at RT for 2 hr,evaporated, purified by flash chromatography(methylenechloride/methanol, 15/1 saturated by 28% aqueous ammonia) andrecrystallization in 50 ml ethyl acetate to give 4 g Example 45 as awhite solid.

1H NMR (400 MHz, DMSO-d₆) δ 2.63 (4H, m), 3.25-3.5 (4H, m), 3.96 (2H,dd), 4.2 (1H, d), 4.43 (1H, d), 7.36 (1H, dt), 7.5 (1H, d), 7.75 (2H,m), 8.03 (1H, dd), 8.07 (1H, s).

MS:M+H=375, M+Na=397

Example 46 Compound Id:2-(2-benzofuran-2-yl-phenylmethanesulfinyl)-N,N-dimethyl acetamide

A mixture of Example 20 (1 g, 3.1 mmol) in acetic acid (10 ml) and 30%H₂O₂ (0.35 ml) was stirred at RT for 4 hr to give a solution that wasevaporated. The flash chromatography (methylenechloride/methanol, 20/1)furnished 0.71 g of Example 46 as a white solid.

1H NMR (400 MHz, CHCl₃) δ 2.95 (6H, s), 3.9 (2H, dd), 4.47 (1H, d), 4.7(1H, d), 7.31 (2H, m), 7.43 (1H, m), 7.5 (3H, m), 7.75 (1H, d), 7.93(2H, d).

MS:M+Na=364.

Example 47 Compound Id:2-(3-phenyl-benzo[b]thiophen-2-ylmethanesulfinyl)-1-pyrrolidin-1-yl-ethanone

To a solution of Example 27 (1.76 g, 4.8 mmol) in glacial acetic acid (5mL), 35% aqueous hydrogen peroxide (0.5 mL) was added. The mixture wasstirred until no more starting material was detected (TLC). After a 3h-stirring, the reaction mixture was concentrated, the resulting oil wasdiluted with water and ethyl acetate (50 mL). The organic layer waswashed successively with water (25 mL), aqueous NaHCO₃ (25 mL), water(25 mL) and dried over Na₂SO₄. On concentration, the solution generateda yellow oil that was purified by column chromatography (CH₂Cl₂/CH₃OH9.6/0.4) to give 0.638 g of Example 47 (white meringue; yield=35%).

¹H-NMR (DMSO) δ (ppm): 8.05 (d, 1H), 7.6-7.35 (m, 8H), 4.45 (q, 2H),3.95 (q, 2H), 3.4 (m, 2H), 3.25 (m, 2H) 1.9-1.7 (m, 4H).

MS:M+H=384

The following examples were prepared according to the process asdescribed for Example 47: following Scheme B Step 3 Pathway E

Example 48 Compound Id:N,N-dimethyl-2-(3-phenyl-benzo[b]thiophen-2-ylmethanesulfinyl)-acetamide

Reagents: Example 28 (2.24 g, 6.5 mmol) in glacial acetic acid (6.5 mL)and 35% aqueous hydrogen peroxide (0.66 mL).

The crude product that was purified by column chromatography(CH₂Cl₂/CH₃OH 9.6/0.4) to give 0.38 g of Example 48 (white meringue;yield=16.4%).

¹H-NMR (DMSO) δ (ppm): 8.05 (d, 1H), 7.6-7.35 (m, 8H), 4.45 (q, 2H),4.05 (s, 2H), 2.95 (s, 3H), 2.8 (s, 3H).

MS:M+Na=380, 2M+Na=737

Example 49 Compound Id:N-isopropyl-2-(3-phenyl-benzo[b]thiophen-2-ylmethanesulfinyl)-acetamide

Reagents: Example 29 (0.62 g, 1.8 mmol) in glacial acetic acid (5 mL)and 35% aqueous hydrogen peroxide (0.2 mL).

Solvant evaporation generated a yellow oil that crystallized slowly onstanding. The residue was stirred with diisopropyl oxyde, filtered anddried in vacuo to give 0.48 g of Example 49 (white powder; yield=72%).

¹H-NMR (DMSO) δ (ppm): 8.2 (d, 1H), 8.05 (d, 1H), 7.55-7.35 (m, 8H), 4.4(q, 2H), 3.8 (h, 1H), 3.65 (q, 2H), 1 (t, 6H).

MS:M+Na=394, M+K=410

Example 50 Compound Id:-(4-hydroxy-piperidin-1-yl)-2-(3-phenyl-benzo[b]thiophen-2ylmethanesulfinyl)ethanone

Reagents: Example 30 (1.1 g, 2.77 mmol) in glacial acetic acid (3 mL)and 35% aqueous hydrogen peroxide (0.3 mL).

The crude product that was purified by column chromatography(CH₂Cl₂/CH₃OH 9.5/0.5) to give 0.625 g of Example 50 (white meringue;yield=56%).

¹H-NMR (DMSO) δ (ppm): 8.05 (d, 1H), 7.6-7.35 (m, 8H), 4.75 (t, 1H), 4.4(q, 2H), 4.2-4 (m, 2H), 3.85 (m, 1H), 3.75-3.55 (m, 2H), 3.2 (m, 1H),3.05 (m, 1H), 1.7 (m, 2H), 1.4 (m, 1H), 1.25 (m, 1H).

MS:M+H=414

Example 51 Compound Id:1-(4-acetyl-piperazin-1-yl)-2-(3-phenyl-benzo[b]thiophen-2-ylmethanesulfinyl)-ethanone

Reagents: Example 31 (1.38 g, 3.25 mmol) in glacial acetic acid (4 mL)and 35% aqueous hydrogen peroxide (0.34 mL).

The crude product that was purified by column chromatography(CH₂Cl₂/CH₃OH 9.2/0.8) to give 1.01 g of Example 50 (white meringue;yield=70%).

¹H-NMR (DMSO) δ (ppm): 8.05 (d, 1H), 7.6-7.35 (m, 8H), 4.45 (q, 2H),4.15 (q, 2H), 3.4 (m, 8H), 2 (s, 3H).

MS:M+Na=463

Example 52 Compound IdN-(2-hydroxy-ethyl)-2-(3-phenyl-benzo[b]thiophen-2-ylmethanesulfinyl)-acetamide

Reagents: Example 32 (0.72 g, 2 mmol) in glacial acetic acid (3 mL) and35% aqueous hydrogen peroxide (0.23 mL).

The crude product was purified by column chromatography (CH₂Cl₂/CH₃OH9.2/0.8) to give after washing in diisopropyl oxyde 0.478 g of Example52 (white powder; yield=64%).

¹H-NMR (DMSO) δ (ppm): 8.25 (t, 1H), 8.05 (d, 1H), 7.6-7.35 (m, 8H), 4.7(t, 1H), 4.4 (q, 2H), 3.7 (q, 2H), 3.4 (m, 2H), 3.15 (m, 2H)

MS:M+Na=396

Example 53 Compound Id:1-[4-(3-Phenyl-benzo[1,4]dioxin-2-ylmethanesulfinylmethyl)-piperazin-1-yl]-ethanone

To a solution of Example 33 (0.78 g, 1.84 mmol) in 3.6 mL of aceticacid, was added 30% aqueous hydrogen peroxide (0.20 mL). After 4 h ofstirring at room temperature, the mixture was neutralized with aqueousNaHCO₃ and then extracted with CH₂Cl₂ (2×70 mL). The organic layer wasdried over MgSO₄ and concentrated to afford the crude product which waspurified by column chromatography (CH₂Cl₂/MeOH 98/2) to give 0.60 g(yield=74%) of Example 53 (white powder).

¹H-NMR (400 MHz, CDCl₃): δ 2.10 (3H, d), 3.3-4.1 (12H, m), 6.6-6.9 (4H,m), 7.3-7.7 (5H, m).

MS:M+Na=463; M+K=479

Examples 54 throught 150 were prepared following the same multistepgeneral method as described in scheme B utilizing the appropriatesubstituted amine —NR¹²R¹³ in Steps 2 or 3. The analytical data as wellas the synthetic pathway used are presented by each compounds molecularformula and masse spectrum (M+H) or (M+Na) are shown in the followingTable 2.

TABLE 2 SYNTHETIC Example n^(o) MF MS PATHWAY 54 C₁₇H₁₇NO₃S M + H = 316A M + Na = 338 55 C₁₉H₁₉NO₃S M + H = 342 A M + Na = 364 56 C₁₈H₁₉NO₃SM + H = 330 A M + Na = 352 57 C₁₉H₂₀N₂O₃S M + H = 357 C M + Na = 379 58C₂₁H₂₂N₂O₄S M + H = 399 C M + Na = 421 59 C₁₇H₁₇NO₄S M + Na = 354 C 60C₂₀H₂₁NO₄S M + H = 372 C M + Na = 394 61 C₁₉H₂₁NO₅S M + Na = 398 C M +K=414 62 C₂₀H₂₀N₂O₄S M + H = 385 C M + Na = 407 M + K=423 63 C₂₄H₂₈N₂O₅SM + H = 457 D M + Na = 479 64 C₂₀H₂₂N₂O₃S M + H = 371 D M + Na = 393 65C₂₁H₂₄N₂O₃S M + H = 385 D M + Na = 407 66 C₂₂H₂₆N₂O₃S M + H = 399 D M +Na = 421 67 C₁₉H₂₀N₂O₄S M + H = 373 D M + Na = 395 M + K=411 68C₁₉H₂₁NO₄S M + H = 360 D M + Na = 382 M + K=398 69 C₁₉H₁₉NO₄S M + H =358 D M + Na = 380 M + K=396 70 C₁₉H₁₈N₂O₄S M + H = 371 D 71 C₂₃H₂₇N₃O₄SM + H = 442 D M + Na = 464 72 C₂₀H₂₁N₃O₄S M + H = 400 D 73 C₂₄H₂₇N₃O₄SM + H = 454 D 74 C₂₂H₂₅N₃O₄S M + H = 428 D 75 C₂₇H₂₆N₂O₅S M + H = 491 D76 C₁₆H₁₅NO₃S M + H = 302 C 77 C₂₀H₂₂N₂O₃S M + H = 371 C M + Na = 393 78C₂₂H₂₄N₂O₄S M + H = 413 D 79 C₂₂H₂₄N₂O₄S M + H = 413 D M + Na = 435 80C₂₁H₂₄N₂O₃S M + H = 385 C 81 C₂₂H₂₆N₂O₃S M + H = 399 C 82 C₂₁H₂₄N₂O₄SM + H = 401 C 83 C₁₄H₁₂O₂S M + H = 245 M + Na = 267 84 C₁₉H₁₉N₂O₃SCl M +H = 391 E M + Na = 413 85 C₂₁H₂₁N₂O₄SCl M + H = 433 E M + Na = 455 86C₁₅H₁₂NO₃SCl M + Na = 344 E 87 C₂₀H₂₂N₂O₄S M + H = 387 E M + Na = 409 88C₂₂H₂₄N₂O₅S M + Na = 451 E M + K=467 89 C₂₁H₂₁N₂O₄SF M + H = 417 E M +Na = 439 90 C₁₅H₁₂NO₃SCl M + Na = 344 E 91 C₁₅H₁₂NO₃SF M + Na = 328 E 92C₂₁H₂₁N₂O₄SCl M + H = 433 E M + Na = 455 93 C₂₁H₂₁N₂O₄SF M + H = 417 EM + Na = 439 94 C₂₁H₂₀N₂O₄SClF M + Na = 362 E 2M + Na = 701 95C₁₇H₁₇NO₄S M + Na = 354 E 96 C₁₅H₁₃NO₃S M + Na = 310 E 97 C₂₁H₂₂N₂O₄SM + Na = 421 E M + K=437 98 C₂₀H₂₁NO₄S M + Na = 394 E M + K=410 99C₁₉H₂₀N₂O₃S M + H = 357 E 100 C₂₁H₂₄N₂O₃S M + H = 385 E 101 C₂₂H₂₄N₂O₄SM + H = 413 F M + Na = 435 102 C₂₂H₂₆N₂O₃S M + H = 399 E 103 C₂₁H₂₄N₂O₄SM + H = 401 E 104 C₂₁H₂₄N₂O₄S M + H = 401 E M + Na = 423 105 C₁₉H₂₀N₂O₃SM + H = 357 E M + Na = 379 106 C₁₉H₂₀N₂O₃S M + H = 357 E M + Na = 379107 C₂₁H₂₂N₂O₄S M + H = 399 E M + Na = 421 108 C₂₁H₂₂N₂O₃S₂ M + H = 415E M + Na = 437 109 C₂₂H₂₄N₂O₄S₂ M + H = 445 E M + Na = 467 110C₂₁H₂₂N₂O₃S₂ M + H = 415 E M + Na = 437 111 C₁₈H₁₉NO₃S M + H = 330 E M +Na = 352 112 C₂₂H₂₄N₂O₃S M + H = 397 E M + Na = 419 113 C₂₁H₂₃NO₃S M + H= 370 E M + Na = 392 114 C₁₆H₁₅NO₂S M + Na = 308 E M + K=324 115C₂₂H₂₆N₂O₃S M + H = 399 E M + Na = 421 116 C₂₀H₂₂N₂O₂S M + H = 355 E M +Na = 377 117 C₁₆H₁₅NO₂S M − H = 284 E M + Na = 308 118 C₁₈H₁₉NO₂S M + H= 314 E M + Na = 336 119 C₂₀H₂₁NO₂S M + H = 340 E M + Na = 362 120C₁₉H₂₁NO₂S M + H = 328 E M + Na = 350 121 C₁₈H₁₉NO₃S M + Na = 352 E M +K=368 122 C₂₁H₂₃NO₃S M + H = 370 E M + Na = 392 123 C₂₂H₂₄N₂O₃S M + Na =419 E 124 C₁₆H₁₅NO₂S M + H = 286 E 125 C₁₈H₁₉NO₂S M + H = 314 E 126C₁₉H₂NO₂S M + H = 328 E 127 C₁₈H₁₉NO₃S M + Na = 352 E 128 C₂₁H₂₃NO₃S M +H = 370 E M + Na = 392 129 C₂₂H₂₄N₂O₃S M + H = 397 E M + Na = 419 130C₂₀H₂₂N₂O₂S M + H = 355 E M + Na = 377 131 C₂₁H₂₂N₂O₃S M + H = 383 E M +Na = 405 M + K=421 132 C₁₇H₁₅NO₃S M + Na = 336 G 133 C₂₁H₂₁NO₃S M + H =368 G 2M + Na = 757 134 C₁₈H₁₇NO₃S M + Na = 350 G 135 C₂₂H₂₃NO₃S M + H =382 G M + Na = 404 136 C₂₀H₂₁NO₃S M + H = 356 G M + Na = 378 137C₂₀H₂₁NO₃S M − H = 354 G M + Na = 378 138 C₂₁H₂₃NO₃S M + H = 370 G M +Na = 392 139 C₂₃H₂₄N₂O₄S M + H = 425 G M + Na = 427 M + K=463 140C₂₄H₂₆N₂O₄S M + Na = 461 G 141 C₁₇H₁₅NO₂S₂ M + Na = 352 G 142 C₂₀H₂₁NO₄SM + Na = 394 G M + K=410 143 C₁₇H₁₅NO₄S M + Na = 352 G 2M + Na = 681 144C₁₇H₁₃Cl₂NO₄S M + Na = 420 G 2M + Na = 817 145 C₂₃H₂₂Cl₂N₂O₅S M + Na =531 G

Example 146 Compound Id:1-(4-acetyl-piperazin-1-yl)-2-(8-chloro-dibenzofuran-2-ylmethanesulfonyl)-ethanone

To a solution of Example 23 (1 g, 2.4 mmol) in acetic acid (15 ml) andTFA (1.5 ml), was added 30% H₂O₂ (0.8 ml, 7.8 mmol). The mixture wasstirred at 50° C. for 5 h, then evaporated to dryness. Water (100 ml)was added and heated at 80° C. to give a suspension that was filteredwhile hot, rinsed by water, dried in vacuum at 50° C. The crude productwas recrystallized in acetonitrile (30 ml) and water (5 ml) to give 0.79g of Example 146 as a white solid.

1H NMR (400 MHz, DMSO-d₆) δ 2.0 (3H, s), 3.5 (8H, m), 4.5 (2H, d), 4.8(2H, d), 7.65 (2H, t), 7.75 (2H, m), 8.2 (1H, s), 8.35 (1H, s).

MS:M+Na=471

Were also synthetized according to Pathway G (Scheme B):

Example 147 Compound Ia: Ethyl2-{[(3-phenyl-1H-indol-2-yl)methyl]sulfanyl}acetate

A 250 mL round-bottom flask containing a magnetic stirring bar equippedwith a reflux condenser was charged with 1.6 g (0.00717 mol) of compound62, 0.8 mL (0.00717 mol) of thioglycolic acid and 50 mL of1,2-dichloroethane. At 0° C., 1.4 mL (0.0107 mol) of BF₃.Et₂O dissolvedin 10 mL of 1,2-dichloroethane was added slowly. The resulting mixturewas stirred for 15 minutes and then 100 mL of water and 10 mL of HCl(1N) were added. The product was extracted with 2×50 mL of ethylacetate. The organic layer was dried over magnesium sulfate, filteredand evaporated to dryness. The crude product was used for the next step(preparation of Example 148).

Example 148 Compound Ic:2-{[(3-phenyl-1H-indol-2-yl)methyl]sulfanyl}acetamide

A 250 mL round-bottom flask containing a magnetic stirring bar equippedwith a reflux condenser was charged with the crude ester Example 147,100 mL of ethanol and 50 mL of an aqueous solution of NH₃ (28%). Themixture was stirred for 5 days and then evaporated to dryness. Afterchromatographic purification (ethyl acetate/petroleum ether: 9/1), weobtained 0.6 g (296.38 g·mol⁻¹) of Example 148.

1H NMR (400 MHz, CDCl₃) δ 3.16 (2H, s) 4.03 (2H, s) 5.52 (1H, bs) 5.93(1H, bs) 7.12 (1H, m) 7.20 (1H, m) 7.25 (1H, m) 7.39 (2H, m) 7.42 (2H,m) 7.54 (1H, m) 8.29 (1H, bs).

Example 149 Compound Id:2-{[(3-phenyl-1H-indol-2-yl)methyl]sulfinyl}acetamide

A 100 mL round-bottom flask containing a magnetic stirring bar equippedwith a reflux condenser was charged with 0.6 g (0.00202 mol) of Example148, 50 mL of methanol, 10 mL of water and 0.48 g (0.00223 mol) ofsodium periodate. The reaction mixture was stirred for 16 hours at 0° C.After evaporation to dryness, the resulting mixture was treated with 100mL of water, triturated for 30 minutes, filtered and dried. Wereobtained 0.50 g (312.38 g·mol⁻¹) of the expected Example 149.

Yield: 79%.

1H NMR (400 MHz, CDCl₃) δ 3.34 (2H, s) 3.67 (1H, dd) 4.34 (1H, dd) 7.04(1H, m) 7.16 (1H, m) 7.32 (1H, m) 7.39 (1H, bs) 7.47 (3H, m) 7.55 (1H,m) 7.75 (2H, m) 11.45 (1H, bs). m/z 335 [M+Na⁺], m/z 351 [M+K⁺].

8) Synthesis of Compounds Ia, Ib and Ic via Scheme B Pathway I Example150 Compound Ic: 2-(7-chlorodibenzofuran-1-ylmethylsulfanyl)acetamide

To a solution of 7-chloro-1-bromomethyl-dibenzofuran (compound 1b; 7.63g, 25.9 mmole) in 80 ml of DMF, were added ethyl thioglycolate (2.75 g,25.94 mmole) and potassium carbonate (4 g, 29 mmole). The mixture waskept at 40-50° C. for 30 minutes. Water (500 mL) was added to give asuspension which was extracted by 2×100 mL dichloromethane, the extractswere washed by water, dried over sodium sulfate, evaporated to give 8.9g of 2-(7-chlorodibenzofuran-1-ylmethylsulfanyl)acetic acid ethyl ester(compound Ia). This compound is pure enough for the next step withoutfurther purification.

A suspension of 2-(7-chlorodibenzofuran-1-ylmethylsulfanyl)acetic acidethyl ester (Compound Ic; 3.77 g, 11.8 mmole) in 50 ml 7Nmethanol/ammonia was stirred at 45° C. for one hour, and then at RT for2 days. The suspension was filtered, washed by methanol, dried in vacuumto give 2.56 g of white solid.

1H NMR (400 MHz, DMSO-d₆) δ 3.1 (2H, s), 4.37 (2H, s), 7.1 (1H, bs),7.33 (1H, d), 7.5 (3H, m), 7.67 (1H, d), 7.93 (1H, s), 8.2 (1H, d).

Example 151 Compound Id:2-(7-chlorodibenzofuran-1-ylmethylsulfinyl)acetamide

To a suspension of 2-(7-chlorodibenzofuran-1-ylmethylsulfanyl)acetamide(Example 151 2.56 g, 8.38 mmole) in acetic acid (90 mL), were added 1.4mL of 35% hydrogen peroxide (14.4 mmole). The mixture was heated at 50°C. for 30 minutes to give a solution, then stirred at RT for 24 hours togive a thick suspension which was filtered, washed by ethanol, ether,dried in vacuum to give 2 g of white solid.

1H NMR (400 MHz, DMSO-d₆) δ 3.7 (1H, d), 3.93 (1H, d), 4.6 (1H, d), 4.72(1H, d), 7.37 (1H, d), 7.45 (2H, m), 7.57 (1H, t), 7.75 (1H, d), 7.78(1H, bs), 7.93 (1H, s), 8.32 (1H, d).

MS:M+Na=344, 2M+Na=665

Examples 153 throught 154 were prepared following the same multistepgeneral method as described in scheme B utilizing the appropriatesubstituted amine —NR¹²R¹³ in Steps 2 and 3. The analytical data as wellas the synthetic pathway used are presented by each compounds molecularformula and masse spectrum (M+H) or (M+Na) are shown in the followingTable 3.

TABLE 3 Example SYNTHETIC n^(o) MF MS PATHWAY 153 C₁₅H₁₂ClNO₃S M + Na =344 I 2M + Na = 665 154 C₁₅H₁₁Cl₂NO₃S M + Na = 378 I 2M + Na = 735Biological DataMethodology: Evaluation of Wake Promoting Activity in Rats

The methodology utilized for evaluating wake promoting activity of testcompounds is based on that described by Edgar and Seidel, Journal ofPharmacology and Experimental Therapeutics, 283:757-769, 1997, andincorporated herein in its entirety by reference.

Animal Surgery. Adult, male Wistar rats (275-320 g from Charles RiverLaboratories, Wilmington, Mass.) were anesthetized (Nembutal, 45 mg/kg,ip.) and surgically prepared with implants for recording of chronic EEG(encephalographic) and EMG (electromyographic) recording. The EEGimplants were made from commercially available components (Plastics One,Roanoke, Va.). EEG signals were recorded from stainless steel screwelectrodes: 2 frontal (+3.0 mm AP from bregma, ±2.0 mm ML), and 2occipital (−4.0 mm AP from bregma, ±2.0 mm ML). Two Teflon-coatedstainless steel wires were positioned under the nuchal trapezoid musclesfor EMG recording. All electrode leads were inserted into a connectorpedestal and the pedestal affixed to the skull by application dentalacrylic. Antibiotic was administered post surgically and antibioticcream was applied to the wound edges to prevent infection. At least oneweek elapsed between surgery and recording.

Recording environment. Postsurgically, rats were housed in pairs in anisolated room. Food and water were available ad libitum, ambienttemperature was 21° C., and humidity was 55%. At least 24 hrs prior torecording, they were placed in Nalgene containers (31×31×31 cm) with awire-grid top, and entry to the room was prohibited during the day ofrecording except for dosing. The containers were placed on a rack withtwo shelves, 4 containers per shelf. Fluorescent overhead room lightswere set to a 24 hr. light/dark cycle (on at 7 AM, off at 7 PM). Lightlevels inside the containers were 38 and 25 lux for the top and bottomshelves respectively. Background white-noise (68 db inside thecontainers) was present in the room to mask ambient sounds.

Data acquisition. EEG and EMG signals were led via cables to acommutator (Plastics One) and then to pre-amplifiers (model 1700, A-MSystems, Carlsborg, Wash.). EEG and EMG signals were amplified (10 K and1 K respectively) and bandpass filtered between 0.3 and 500 Hz for EEGand between 10 and 500 Hz for EMG. These signals were digitized at 128samples per second using ICELUS sleep research software (M. Opp, U.Texas; see Opp, Physiology and Behavior 63:67-74, 1998, and Imeri,Mancia, and Opp, Neuroscience 92:745-749, 1999, incorporated byreference herein in their entirety) running under Labview 5.1 softwareand data acquisition hardware (PCI-MIO-16E-4; National Instruments,Austin, Tex.). On the day of dosing, data was recorded for 6 to 10 hoursbeginning at 11 AM.

Drug administration and study design. Compounds were evaluated on groupsof from 4 to 8 rats carried out over one or two separate test sessions.Each animal was tested with a different compound or vehicle for up to 10weeks with at least 7 days between successive tests. A vehicle group wasincluded in all experiments, and each animal received vehicle every4^(th) test. Test compounds were suspended in sterile 0.25%methylcellulose (pH=6.2; Upjohn Co., Kalamazoo, Mich.) at 30 mg/mL.Although compounds can be administered at dosages greater than 100 mg/kgand are expected to be active under the selection criteria of dataanalysis, unless otherwise noted, compounds were administered at asingle dose of 100 mg/kg. Dosing was carried out at noon, while the ratswere predominantly asleep. Each rat was lifted out of its container,given an intraperitoneal injection in a volume of 5 mL/kg, and replaced.Dosing required approximately 30 sec per rat.

Sleep/wake scoring. Sleep and wake activity were determined manuallyusing ICELUS software. This program displays the EEG and EMG data inblocks of 6 sec along with the EEG frequency spectrum. Arousal state wasscored as awake, rapid eye-movement (REM), or slow-wave or non-REM sleep(NREM) according to visual analysis of EEG frequency and amplitudecharacteristics and EMG activity (Opp and Krueger, 1994; Van Gelder, etal., 1991; Edgar, et al., 1991, 1997; Seidel, et al, 1995, incorporatedby reference herein in their entirety). Essentially, waking activityconsists of relatively low-amplitude EEG activity with relatively lowerpower in the frequency band from 0.5-6 Hz, accompanied by moderate tohigh level EMG activity. In a particular waking state (“theta-waking”),EEG power can be relatively focused in the 6-9 Hz (theta) range, butsignificant EMG activity is always present. NREM sleep is characterizedby relative high-amplitude EEG activity with relatively greater power inthe low frequency band from 0.5-6 Hz, accompanied by little or no EMGactivity. REM sleep is characterized by moderate and constant amplitudeEEG focused in the theta (6-9 Hz) range, similar to waking theta, butwith no EMG activity.

Data analysis and statistics. Two basic outcome measures were used toascertain whether a compound exhibited wake-enhancing activity. Thefirst was the percent time spent awake for each 30 min period followingdosing. The second was the total time spent awake in the first 3 hrsfollowing dosing (3 hr AUC; maximum 180 min). For purposes ofascertaining activity of a test compound, wake activity values werecompared against corresponding vehicle values. The vehicle values wereof two types. The first type was the corresponding within-experimentvehicle, that is, a value for the vehicle group run concurrently withthe test compound. A second “reference” vehicle value consisted of themean 3 hr AUC value calculated from 234 animals in 59 separateexperiments carried out during the same time period as the evaluationsof the test compounds (mean±SD=69.22±20.12; 95% confidencelimits=66.63-71.81). Two-tailed, unpaired t-tests were performed on thewake time values for drug versus vehicle treated animals, and compoundswith p<0.05 were deemed significantly wake-promoting. A test compoundwas considered “active” if it met one of the following three criteria.

-   -   (i) The 3 hr AUC value for the test compound was significantly        greater (p<0.05) than the mean wake value for the reference        vehicle group (N=234).    -   (ii) The 3 hr AUC value for the test compound was significantly        greater (p<0.05) than the corresponding value for the vehicle        group within the same experiment.    -   (iii) One or more of the half-hour wake time values from 0.5 to        2 hrs after dosing was significantly greater (p<0.05) in the        test compound group than in the corresponding vehicle group        within the same experiment.

Results:

Compounds of the inventionn either have demonstrated or are expected todemonstrate utility for wake promoting activity.

As an example, the three-hours AUC values (mean±sem) for the referencevehicle group and for the test compounds are reported Table 4 forExamples 26, 99 and 130. These test compounds were administered by i.p.route at a 100 mg/kg dose and the time-course of the percent of timeawake as function of time was estimated from 1 hr prior to 5 hours postdosing.

TABLE 4 Mean AUC 0-3 h values (±sem) for the reference vehicle group andfor test compounds Test Vehicle compound Mean sem Mean sem p Example 2673.6 7.7 132.0 13.2 0.002 Example 99 53.0 3.3 129.1 17.3 0.022 Example130 76.2 17.5 149.2 2.9 0.006 AUC 0-3 h (% of waiking time × hr) − n = 4Rats per test compound and 8 rats per control groups.

As compared to the control groups, compounds of Example 26, 99 and 130produced a significantly greated wakefulness than that observed in thevehicle-treated animals (p<0.05).

References. The following references, to the extent that they provideexemplary procedural or other details supplementary to those set forthherein, are specifically incorporated in their entirety herein byreference:

-   Touret, et al., Neuroscience Letters, 189:43-46, 1995.-   Van Gelder, R. N. et al., Sleep 14:48-55, 1991.-   Edgar, D. M., J. Pharmacol. Exp. Ther. 282:420-429, 1997.-   Edgar and Seidel, J. Pharmacol. Exp. Ther., 283:757-69, 1997.-   Hernant et al., Psychopharmacology, 103:28-32, 1991.-   Lin et al., Brain Research, 591:319-326, 1992.-   Opp and Krueger, American Journal of Physiology 266:R688-95, 1994-   Panckeri et al., Sleep, 19(8):626-631, 1996.-   Seidel, W. F., et al., J. Pharmacol. Exp. Ther. 275:263-273, 1995.-   Shelton et al., Sleep 18(10):817-826, 1995.-   Welsh, D. K., et al., Physiol. Behav. 35:533-538, 1985.    Utility

The present invention provides a method of treating diseases andconditions in a subject in need thereof comprising administering to saidsubject a therapeutically effective amount of a compound of formula (I).For example, the compounds of of the present invention are use in thetreatment of diseases, including treatment of sleepiness, promotion ofwakefulness, treatment of Parkinson's disease, cerebral ischemia,stroke, sleep apneas, eating disorders, stimulation of appetite andweight gain, treatment of attention deficit hyperactivity disorder(“ADHD”), enhancing function in disorders associated withhypofunctionality of the cerebral cortex, including, but not limited to,depression, schizophrenia, fatigue, in particular, fatigue associatedwith neurologic disease, such as multiple sclerosis, chronic fatiguesyndrome, and improvement of cognitive dysfunction.

Dosage and Formulation

The compounds of the present invention can be administered fortherapeutic purposes by any means that results in the contact of theactive agent with the agent's site of action in a subject. The compoundsmay be administered by any conventional means available for use inconjunction with pharmaceuticals, either as individual therapeuticagents or in a combination with other therapeutic agents, such as, forexample, analgesics, or in combination with antidepressants, includingbut are not limited to tricyclic antidepressants (“TCAs”), SelectiveSerotonin Reuptake Inhibitors (“SSRIs”), Serotonin and NoradrenalineReuptake Inhibitors (“SNRIs”), Dopamine Reuptake Inhibitors (“DRIs”),Noradrenaline Reuptake Inhibitors (“NRUs”), Dopamine, Serotonin andNoradrenaline Reuptake Inhibitors (“DSNRIs”) and Monoamine OxidaseInhibitors (“MAOIs) including reversible inhibitors of monoamine oxidasetype A (RIMAs). The compounds of the present invention are preferablyadministered in therapeutically effective amounts for the treatment ofthe diseases and disorders described herein.

A therapeutically effective amount can be readily determined by theattending diagnostician, as one skilled in the art, by the use ofconventional techniques. The effective dose will vary depending upon anumber of factors, including the pharmacodynamics of the active agent,the type and extent of progression of the disease or disorder, the age,weight and health of the particular patient, the formulation of theactive and its mode and frequency of administration, and the desiredeffect with a minimization of side effects. Typically, the compounds areadministered at lower dosage levels, with a gradual increase until thedesired effect is achieved.

Typical dose ranges are from about 0.01 mg/kg to about 100 mg/kg of bodyweight per day, with a preferred dose from about 0.01 mg/kg to 10 mg/kgof body weight per day. A typical daily dose for adult humans can rangefrom about 1 to about 1000 mg of the active agent, particularly fromabout 1 to about 400 mg, and including 25, 50, 85, 100, 150, 170, 200,255, 250, 255, 340, 400, 425, 500, 600, 700, 750, 800, and 900 mg doses,and equivalent doses for a human child.

The compounds may be administered in one or more unit dose forms, andthey may be administered in a single daily dose or in two, three or fourdoses per day. The unit dose ranges from about 1 to about 1000 mg,particlularly from about 1 to about 400 mg, and including 25, 50, 85,100, 150, 170, 200, 255, 250, 255, 340, 400, 425, 500, 600, 700, 750,800, and 900 mg unit doses, and equivalent unit doses for a human child.In particular, the unit dosages range from about 1 to about 500 mgadministered one to four times a day, preferably from about 10 mg toabout 300 mg, two times a day. In an alternate method of describing aneffective dose, an oral unit dose is one that is necessary to achieve ablood serum level of about 0.05 to 20 μg/ml in a subject, and preferablyabout 1 to 20 μg/ml.

The compounds of the present invention may be formulated intopharmaceutical compositions by admixture with one or morepharmaceutically acceptable excipients. The active agent may be presentin about 0.5-95% by weight of the composition. The excipients areselected on the basis of the chosen route of administration and standardpharmaceutical practice, as described, for example, in Remington: TheScience and Practice of Pharmacy, 20^(th) ed.; Gennaro, A. R., Ed.;Lippincott Williams & Wilkins: Philadelphia, Pa., 2000.

The compositions can be prepared for administration by oral means,including tablets, pills, powders, capsules, troches and the like;parenteral means, including intravenous, intramuscular, and subcutaneousmeans; topical or transdermal means, including patches, creams,ointments, lotions, pastes, gels, solutions, suspensions, aerosols, andpowders and the like; transmucosal means, including nasal, rectal,vaginal, sublingual and buccal means; ophthalmic or inhalation means.Preferably the compositions are prepared for oral administration,particularly in the form of tablets, capsules or syrups; parenteraladministration, particularly in the form of liquid solutions,suspensions or emulsions; intranasal administration, particularly in theform of powders, nasal drops, or aerosols; or for topical use, such aspatches, creams, ointments, and lotions.

For oral administration, the tablets, pills, powders, capsules, trochesand the like can contain one or more of the following: diluents orfillers such as starch, or cellulose; binders such as microcrystallinecellulose, gelatins, or polyvinylpyrrolidone; disintegrants such asstarch or cellulose derivatives; lubricants such as talc or magnesiumstearate; glidants such as colloidal silicon dioxide; sweetening agentssuch as sucrose or saccharin; and flavoring agents such as peppermint orcherry flavoring. Capsules may contain any of the above ingredients, andmay also contain a semi-solid or liquid carrier, such as a polyethyleneglycol. The solid oral dosage forms may have coatings of sugar, shellac,or enteric agents. Liquid preparations may be in the form of aqueous oroily suspensions, solutions, emulsions, syrups, elixirs, etc., or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as surfactants, suspending agents,emulsifying agents, diluents, sweetening and flavoring agents, dyes andpreservatives.

The compositions may also be administered parenterally. Thepharmaceutical forms acceptable for injectable use include, for example,sterile aqueous solutions, or suspensions. Aqueous carriers includemixtures of alcohols and water, buffered media, and the like. Nonaqueoussolvents include alcohols and glycols, such as ethanol, and polyethyleneglycols; oils, such as vegetable oils; fatty acids and fatty acidesters, and the like. Other components can be added includingsurfactants; such as hydroxypropylcellulose; isotonic agents, such assodium chloride; fluid and nutrient replenishers; electrolytereplenishers; agents which control the release of the active compounds,such as aluminum monostearate, and various co-polymers; antibacterialagents, such as chlorobutanol, or phenol; buffers; suspending agents;thickening agents; and the like. The parenteral preparations can beenclosed in ampules, disposable syringes or multiple dose vials. Otherpotentially useful parenteral delivery systems for the active compoundsinclude ethylene-vinyl acetate copolymer particles, osmotic pumps,implantable infusion systems, and liposomes.

Other possible modes of administration include formulations forinhalation, which include such means as dry powder, aerosol, or drops.They may be aqueous solutions containing, for example,polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oilysolutions for administration in the form of nasal drops, or as a gel tobe applied intranasally. Formulations for topical use are in the form ofan ointment, cream, or gel. Typically these forms include a carrier,such as petrolatum, lanolin, stearyl alcohol, polyethylene glycols, ortheir combinations, and either an emulsifying agent, such as sodiumlauryl sulfate, or a gelling agent, such as tragacanth. Formulationssuitable for transdermal administration can be presented as discretepatches, as in a reservoir or microreservoir system, adhesivediffusion-controlled system or a matrix dispersion-type system.Formulations for buccal administration include, for example lozenges orpastilles and may also include a flavored base, such as sucrose oracacia, and other excipients such as glycocholate. Formulations suitablefor rectal administration are preferably presented as unit-dosesuppositories, with a solid based carrier, such as cocoa butter, and mayinclude a salicylate.

The compositions of the present invention may be formulated to controland/or delay the release of the active agent(s). Such controlled-,delayed, sustained-, or extended-release compositions are well-known inthe art, and may include, for example, reservoir or matrix diffusionproducts, as well as dissolution systems. Some compositions may utilize,for example biocompatible, biodegradable lactide polymer,lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylenecopolymers as excipients.

Preferred embodiments of the invention include the following:

1. A compound of formula (A):

wherein

-   Ar is:

-   wherein:    -   U is CH₂, CR²⁵R²⁶, O, S(O)_(y), NR¹⁰, C(═O), C(═S), CHOH,        CHOR¹⁴, C═NOR¹⁴, or C═NNR¹²R¹³;    -   V and W are independently selected from a bond, CH₂, CR²⁵R²⁶, O,        S(O)_(y), NR¹⁰, C(═O), C(═S), CHOH, CHOR¹⁴, C═NOR¹⁴, or        C═NNR¹²R¹³;    -   rings A, B, and C are optionally substituted with one to three        groups selected from F, Cl, Br, I, OR²², OR²⁷, NR²³R²⁴, NHOH,        NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇        cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6        membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,        C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴,        NR²¹C(═S)R²², and S(O)_(y)R²²;    -   ring D is optionally substituted with one group selected from        C₁-C₆ alkyl, phenyl, and 5-10 membered heteroaryl; provided that        when V is a bond, and W is O, S(O)_(y) or NR¹¹, ring D is        substituted by a phenyl group;-   Y is C₁-C₆ alkylene; or (C₁-C₄ alkylene)_(m)-Z-(C₁-C₄ alkylene);    -   wherein said alkylene groups are optionally substituted with one        to three R²⁰ groups;-   Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10    membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered    heterocycloalkylene; wherein said arylene, heteroarylene,    cycloalkylene, and heterocycloalkylene groups are optionally    substituted with one to three R²⁰ groups;-   R¹ is selected from H, NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹,    OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³,    NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, NR²¹S(O)₂NR¹²R¹³, and C(═O)NR¹¹OR²²;-   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl,    C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl and aryl    groups are optionally substituted with one to three R²⁰ groups;-   R¹¹ at each occurrence is independently selected from H, C₁-C₆    alkyl, and C₆-C₁₀ aryl; wherein said alkyl and aryl groups are    optionally substituted with one to three R²⁰ groups;-   R¹² and R¹³ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, C₆-C₁₀ aryl, and NR²³R²⁴, or R¹² and R¹³, together    with the nitrogen to which they are attached, form a 3-7 membered    heterocyclic ring;    -   wherein said alkyl and aryl groups and heterocyclic ring are        optionally substituted with one to three R²⁰ groups;-   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,    C₆-C₁₀ aryl, and alkylaryl; wherein said alkyl, aryl and alkylaryl    groups are optionally substituted with one to three R²⁰ groups;-   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,    OR²², OR²⁷, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl optionally    substituted with OH, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,    3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,    arylalkyl, ═O, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,    NR²¹C(═O)R²², NR²¹C(═O)OR²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and    S(O)_(y)R²²;-   R²¹ at each occurrence is independently selected from H and C₁-C₆    alkyl;-   R²² at each occurrence is independently selected from H, C₁-C₆ alkyl    optionally substituted with OH, arylalkyl and C₆-C₁₀ aryl;-   R²³ and R²⁴ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the    nitrogen to which they are attached, form a 3-7 membered    heterocyclic ring optionally substituted with ═O;-   R²⁵ and R²⁶ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²⁵ and R²⁶, together with the    carbon to which they are attached, form a 3-7 membered heterocyclic    ring;-   R²⁷ at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;-   m is 0 or 1;-   n is 0 or 1;-   q is 0, 1, or 2;-   y is 0, 1, or 2;    with the exclusion of the compounds wherein:    -   U is CH₂, C(═O), CH(CH₃), S or C═NNHPh; and    -   Y is CH₂; and    -   R¹ is H;        and with the exclusion of the compounds wherein:    -   U is CH₂; and    -   Y is C₁-C₆ alkylene optionally substituted with C₁-C₆ alkylene;        and    -   R¹ is CONH₂, or CO₂R¹¹ with R¹¹═H or C₁-C₆ alkyl;        and with the exclusion of the compounds:-   3-[(methylthio)methyl]-2-phenyl-1H-inden-1-one-   3-[(methylsulfinyl)methyl]-2-phenyl-1H-inden-1-one    and the stereoisomeric forms, mixtures of stereoisomeric forms or    pharmaceutically acceptable salts forms thereof.

2. The compound according to claim 1:

wherein

-   Y is C₁-C₆alkylene;    -   (C₁-C₄ alkylene)_(m)-Z¹-(C₁-C₄ alkylene);    -   C₁-C₄ alkylene-Z²-C₁-C₄ alkylene;        -   wherein said alkylene groups are optionally substituted with            one to three R²⁰ groups;-   Z¹ is CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10 membered heteroarylene,    C₃-C₆ cycloalkylene, or 3-6 membered heterocycloalkylene; wherein    said arylene, heteroarylene, cycloalkylene, and heterocycloalkylene    groups are optionally substituted with one to three R²⁰ groups;-   Z² is O, NR^(10A), or S(O)_(y);-   m is 0 or 1;-   n is 0 or 1;-   q is 0, 1, or 2;-   y is 0, 1, or 2;    and the stereoisomeric forms, mixtures of stereoisomeric forms or    pharmaceutically acceptable salts forms thereof.

3. The compound according to any of claims 1 or 2, wherein q is 1.

4. The compound according to any of claims 1 to 3, wherein R¹ is H.

5. The compound according to any of claims 1 to 3, wherein R¹ isselected from NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹,C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹,NR²¹C(═O)NR¹²R¹³, NR²¹S(O)₂NR¹²R¹³, and C(═O)NR¹¹OR²².

6. The compound according to claim 5, wherein R¹ is selected fromNR¹²R¹³, NR²¹C(═O)R¹⁴; C(═O)NR¹²R¹³; C(═NR¹¹)NR¹²R¹³, NR²¹C(═O)NR¹²R¹³.

7. The compound according to claim 6, wherein R¹ is C(═O)NR¹²R¹³.

8. The compound according to any of claims 5 to 7, wherein R¹² and R¹³are each independently selected from H, C₁-C₆ alkyl and NR²³R²⁴.

9. The compound according to any of claims 5 to 7, wherein R¹² and R¹³together with the nitrogen to which they are attached, form a 3-7membered heterocyclic ring, wherein said heterocyclic ring is optionallysubstituted with one R²⁰ group.

10. The compound according to claim 9, wherein said heterocyclic ring isunsubstituted.

11. The compound according to claim 5, wherein R¹ is selected fromC(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹,and NR²¹S(O)₂NR¹²R¹³;

12. The compound according to any of claims 1 to 11, wherein Ar is:

13. The compound according to claim 12, wherein U is CH₂, O, S(O)_(y),or NR¹⁰.

14. The compound according to claim 13, wherein U is CH₂, O or S(O)_(y).

15. The compound according to any of claims 1 to 11, wherein Ar is:

16. The compound according to claim 15, wherein V is O, S(O)_(y) orNR¹¹, W a bond and ring D is substituted with a phenyl.

17. The compound according to claim 15, wherein V is O, W is O and ringD is substituted with a phenyl.

18. The compound according to claims 1 to 17, wherein Y is C₁-C₆alkylene.

19. The compound according to claim 18, wherein Y is CH₂.

20. The compound according to any of claims 2 to 17, wherein Y is (C₁-C₄alkylene)_(m)-Z¹-(C₁-C₄ alkylene)_(n).

21. The compound according to claim 20, wherein Z¹ is C₆-C₁₀ arylene orC₃-C₆ cycloalkylene.

22. The compound according to claim 20, wherein Z¹ is 5-10 memberedheteroarylene or 3-6 membered heterocycloalkylene.

23. The compound according to claim 20, wherein Z¹ is CR²¹═CR²¹ or C≡C.

24. The compound according to any of claims 2 to 17, wherein Y is C₁-C₄alkylene-Z²-C₁-C₄ alkylene.

25. The compound according to claim 24, wherein Z² is O.

26. The compound according to claim 1, with the structure of formula(I):

wherein

-   Ar is:

-   -   U is CH₂, O, S(O)_(y), or NR¹⁰;    -   V and W are independently selected from a bond, O, S(O)_(y), or        NR¹⁰;    -   rings A, B, and C are optionally substituted with one to three        groups selected from F, Cl, Br, I, OR²², OR²⁷, NR²³R²⁴, NHOH,        NO₂, CN, CF₃, C₁-C₆ alkyl, phenyl, arylalkyl, and C(═O)R²²;    -   ring D is optionally substituted with one group selected from        C₁-C₆ alkyl, and phenyl;

-   Y is C₁-C₆ alkylene;    -   C₁-C₄ alkylene-Z¹-(C₁-C₄ alkylene)_(n);    -   C₁-C₄ alkylene-Z²-C₁-C₄ alkylene;        -   wherein said alkylene groups are optionally substituted with            one to three R²⁰ groups;

-   Z¹ is CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10 membered heteroarylene,    -   C₃-C₆ cycloalkylene, or 3-6 membered heterocycloalkylene;        wherein said arylene, heteroarylene, cycloalkylene, and        heterocycloalkylene groups are optionally substituted with one        to three R²⁰ groups;

-   Z² is O, NR^(10A), or S(O)_(y);

-   R¹ is selected from NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹,    C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹,    NR²¹C(═O)NR¹²R¹³, NR²¹S(O)₂NR¹²R¹³, and C(═O)NR¹¹OR²²;

-   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl,    C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl group is optionally    substituted with one to three R²⁰ groups;

-   R¹¹ at each occurrence is independently selected from H, and C₁-C₆    alkyl; wherein said alkyl group is optionally substituted with one    to three R²⁰ groups;

-   R¹² and R¹³ at each occurrence are each independently selected from    H, and C₁-C₆ alkyl, and NR²³R²⁴, or R¹² and R¹³, together with the    nitrogen to which they are attached, form a 3-7 membered    heterocyclic ring;    -   wherein said alkyl group and heterocyclic ring are optionally        substituted with one to three R²⁰ groups;

-   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl    and C₆-C₁₀ aryl; wherein said alkyl, aryl and alkylaryl groups are    optionally substituted with one to three R²⁰ groups;

-   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,    OR²², OR²⁷, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl optionally    substituted with OH, phenyl, ═O, C(═O)R²², CO₂R²², OC(═O)R²²,    C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²²,    and S(O)_(y)R²²;

-   R²¹ at each occurrence is independently selected from H and C₁-C₆    alkyl;

-   R²² at each occurrence is independently selected from H, C₁-C₆ alkyl    optionally substituted with OH, phenyl, and benzyl

-   R²³ and R²⁴ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the    nitrogen to which they are attached, form a 3-7 membered    heterocyclic ring optionally substituted with ═O;

-   R²⁷ at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;

-   n is 0 or 1;

-   q is 0, 1, or 2;

-   y is 0, 1, or 2;    and the stereoisomeric forms, mixtures of stereoisomeric forms or    pharmaceutically acceptable salts forms thereof.

27. The compound according to claim 26, wherein Y is C₁-C₆ alkylene,C₁-C₄ alkylene-Z¹-C₁-C₄ alkylene, or C₁-C₄ alkylene-Z²-C₁-C₄ alkylene,wherein said alkylene groups are optionally substituted with one tothree C₁-C₆ alkyl groups;

-   -   Z¹ is CR²¹═CR²¹, C≡C, or phenyl;    -   Z² is O, NR^(10A), or S(O)_(y);        R¹ is selected from NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹,        C(═O)NR¹²R¹³, and C(═O)NR¹¹OR²².

28. The compound according to claim 27, wherein Y is C₁-C₆ alkylene, orC₁-C₄ alkylene-Z¹-C₁-C₄ alkylene.

29. The compound according to claim 28, wherein Y is C₁-C₆ alkylene.

30. The compound according to any of claims 26 to 29, wherein R¹ isC(═O)NR¹²R¹³.

31. The compound according to claim 30, having the structure of formula(III):

32. The compound according to claim 31, wherein U is CH₂, O, orS(O)_(y).

33. The compound according to claim 32, wherein U is O, or S(O)_(y).

34. The compound according to claim 32, wherein U is CH₂.

35. The compound according to any of claims 31 to 34, wherein Y is C₁-C₆alkylene.

36. The compound according to claim 35, wherein Y is CH₂, or CH₂—CH₂.

37. The compound according to any of claims 31 to 34, wherein Y is C₁-C₄alkylene-Z¹-(C₁-C₄ alkylene), and Z¹ is phenylene, 5-6 memberedheteroarylene, CR²¹═CR²¹, or C≡C.

38. The compound according to claim 37, wherein Y is C₁-C₄alkylene-Z¹-(C₁-C₄ alkylene)_(n) and Z¹ is phenylene, CR²¹═CR²¹, or C≡C.

39. The compound according to claim 30, having the structure of formula(IV)

40. The compound according to claim 39, wherein V is O, S(O)_(y), orNR¹¹, W is a bond and ring D is substituted with a phenyl.

41. The compound according to claim 40, wherein V is O, or S(O)_(y), Wis a bond and ring D is substituted with a phenyl.

42. The compound according to claim 39, wherein V is O, W is O and ringD is substituted with a phenyl.

43. The compound according to any of claims 39 to 42, wherein Y is C₁-C₆alkylene.

44. The compound according to claim 43, wherein Y is CH₂, or CH₂—CH₂.

45. The compound according to any of claims 39 to 42, wherein Y is C₁-C₄alkylene-Z¹-(C₁-C₄ alkylene)_(n) and Z¹ is phenylene, 5-6 memberedheteroarylene, CR²¹═CR²¹, or C≡C.

46. The compound according to claim 45, wherein Y is C₁-C₄alkylene-Z¹-(C₁-C₄ alkylene)_(n) and Z¹ is phenylene, CR²¹═CR²¹, or C≡C.

47. The compound according to claim 1, selected in accordance with thefollowing table:

wherein Ar, q, Y—R¹ are defined in the table below;

Ex. n^(o) Ring Ar q Y—R¹ 16 Dibenzofuran-2-yl 0 CH₂CONH₂ 36Dibenzofuran-2-yl 1 CH₂CONH₂ Dibenzofuran-2-yl 0 CH₂CON(CH₃)₂ 54Dibenzofuran-2-yl 1 CH₂CON(CH₃)₂ Dibenzofuran-2-yl 0CH₂CO—N-pyrrolidinyl 55 Dibenzofuran-2-yl 1 CH₂CO—N-pyrrolidinylDibenzofuran-2-yl 0 CH₂CONHCH(CH₃)₂ 56 Dibenzofuran-2-yl 1CH₂CONHCH(CH₃)₂ Dibenzofuran-2-yl 0CH₂CO-1-(4-tert-butoxycarbonyl)-piperazinyl 57 Dibenzofuran-2-yl 1CH₂CO-1-piperazinyl Dibenzofuran-2-yl 0 CH₂CO-1-(4-acetyl)-piperazinyl58 Dibenzofuran-2-yl 1 CH₂CO-1-(4-acetyl)-piperazinyl Dibenzofuran-2-yl0 CH₂CONHCH₂CH₂OH 59 Dibenzofuran-2-yl 1 CH₂CONHCH₂CH₂OHDibenzofuran-2-yl 0 CH₂CO-1-(4-hydroxy)piperidinyl 60 Dibenzofuran-2-yl1 CH₂CO-1-(4-hydroxy)piperidinyl Dibenzofuran-2-yl 0CH₂CONHCH₂CH₂OCH₂CH₂OH 61 Dibenzofuran-2-yl 1 CH₂CONHCH₂CH₂OCH₂CH₂OH 15Dibenzofuran-2-yl 0 CH₂CO-1-[4-(2-hydroxyethyl)-piperazinyl] 34Dibenzofuran-2-yl 1 CH₂CO-1-[4-(2-hydroxyethyl)-piperazinyl]Dibenzofuran-2-yl 0 CH₂CO-1-(4-formyl)-piperazinyl 62 Dibenzofuran-2-yl1 CH₂CO-1-(4-formyl)-piperazinyl 63 Dibenzofuran-2-yl 1CH₂CO-1-(4-tert-butoxycarbonyl)-piperazinyl 35 Dibenzofuran-2-yl 1CH₂CO-1-(4-ethoxycarbonyl)-piperazinyl 64 Dibenzofuran-2-yl 1CH₂CO-1-(4-methyl)-piperazinyl Dibenzofuran-2-yl 0CH₂CO-1-(4-ethyl)-piperazinyl 65 Dibenzofuran-2-yl 1CH₂CO-1-(4-ethyl)-piperazinyl Dibenzofuran-2-yl 0CH₂CO-1-(4-propyl)-piperazinyl 66 Dibenzofuran-2-yl 1CH₂CO-1-(4-propyl)-piperazinyl Dibenzofuran-2-yl 0 CH₂CON-morpholinyl 67Dibenzofuran-2-yl 1 CH₂CON-morpholinyl Dibenzofuran-2-yl 0CH₂CO—N-ethyl-N-(2-hydroxy-ethyl) 68 Dibenzofuran-2-yl 1CH₂CO—N-ethyl-N-(2-hydroxy-ethyl) Dibenzofuran-2-yl 0CH₂CONHN-morpholinyl 69 Dibenzofuran-2-yl 1 CH₂CONHN-morpholinylDibenzofuran-2-yl 0 CH₂CO-4-(2-oxo-piperazinyl) 70 Dibenzofuran-2-yl 1CH₂CO-4-(2-oxo-piperazinyl) 71 Dibenzofuran-2-yl 1CH₂CO-1-(4-isopropylaminocarbonyl)- piperazinyl 72 Dibenzofuran-2-yl 1CH₂CO-1-(4-aminocarbonyl)-piperazinyl 73 Dibenzofuran-2-yl 1CH₂CO-1-(4-pyrrolidinylcarbonyl)-piperazinyl 74 Dibenzofuran-2-yl 1CH₂CO-1-(4-dimethylaminocarbonyl)- piperazinyl 75 Dibenzofuran-2-yl 1CH₂CO-1-(4-benzyloxycarbonyl)-piperazinyl Dibenzofuran-2-yl 0CH₂CH₂CONH₂ 76 Dibenzofuran-2-yl 1 CH₂CH₂CONH₂ Dibenzofuran-2-yl 0CH₂CH₂CO-1-piperazinyl-N-Boc 77 Dibenzofuran-2-yl 1CH₂CH₂CO-1-piperazinyl 78 Dibenzofuran-2-yl 1CH₂CH₂CO-1-(4-acetyl)-piperazinyl 79 Dibenzofuran-2-yl 1CH₂CON-[3-(2-oxo-pyrrolidin-1-yl)-propyl] Dibenzofuran-2-yl 0CH₂CON-(2-pyrrolidin-1-yl-ethyl) 80 Dibenzofuran-2-yl 1CH₂CON-(2-pyrrolidin-1-yl-ethyl) Dibenzofuran-2-yl 0CH₂CON-(2-piperidin-1-yl-ethyl) 81 Dibenzofuran-2-yl 1CH₂CON-(2-piperidin-1-yl-ethyl) Dibenzofuran-2-yl 0CH₂CON-(2-morpholin-4-yl-ethyl) 82 Dibenzofuran-2-yl 1CH₂CON-(2-morpholin-4-yl-ethyl Dibenzofuran-2-yl 0 H 83Dibenzofuran-2-yl 1 H 6-Chloro-dibenzofuran-2-yl 0CH₂CO-1-piperazinyl-N-Boc 84 6-Chloro-dibenzofuran-2-yl 1CH₂CO-1-piperazinyl 6-Chloro-dibenzofuran-2-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 85 6-Chloro-dibenzofuran-2-yl 1CH₂CO-1-(4-acetyl)-piperazinyl 22 8-Chloro-dibenzofuran-2-yl 0CH₂CO-1-piperazinyl-N-Boc 41 8-Chloro-dibenzofuran-2-yl 1CH₂CO-1-piperazinyl 8-Chloro-dibenzofuran-2-yl 0 CH₂CONH₂ 868-Chloro-dibenzofuran-2-yl 1 CH₂CONH₂ 23 8-Chloro-dibenzofuran-2-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 42 8-Chloro-dibenzofuran-2-yl 1CH₂CO-1-(4-acetyl)-piperazinyl 146 8-Chloro-dibenzofuran-2-yl 2CH₂CO-1-(4-acetyl)-piperazinyl 21 8-Chloro-dibenzofuran-2-yl 0CH₂CO-1-(4-hydroxyethyl)-piperazinyl 40 8-Chloro-dibenzofuran-2-yl 1CH₂CO-1-(4-hydroxyethyl)-piperazinyl 17 8-Methoxy-dibenzofuran-2-yl 0CH₂CONH₂ 37 8-Methoxy-dibenzofuran-2-yl 1 CH₂CONH₂8-Methoxy-dibenzofuran-2-yl 0 CH₂CO-1-piperazinyl-N-Boc 878-Methoxy-dibenzofuran-2-yl 1 CH₂CO-1-piperazinyl8-Methoxy-dibenzofuran-2-yl 0 CH₂CO-1-(4-acetyl)-piperazinyl 888-Methoxy-dibenzofuran-2-yl 1 CH₂CO-1-(4-acetyl)-piperazinyl 268-Fluoro-dibenzofuran-2-yl 0 CH₂CO-1-piperazinyl-N-Boc 458-Fluoro-dibenzofuran-2-yl 1 CH₂CO-1-piperazinyl8-Fluoro-dibenzofuran-2-yl 0 CH₂CO-1-(4-acetyl)-piperazinyl 898-Fluoro-dibenzofuran-2-yl 1 CH₂CO-1-(4-acetyl)-piperazinyl 198-Fluoro-dibenzofuran-2-yl 0 CH₂CONH₂ 38 8-Fluoro-dibenzofuran-2-yl 1CH₂CONH₂ 4-Chloro-dibenzofuran-2-yl 0 CH₂CONH₂ 904-Chloro-dibenzofuran-2-yl 1 CH₂CONH₂ 4-Fluoro-dibenzofuran-2-yl 0CH₂CONH₂ 91 4-Fluoro-dibenzofuran-2-yl 1 CH₂CONH₂4-Chloro-dibenzofuran-2-yl 0 CH₂CO-1-(4-acetyl)-piperazinyl 924-Chloro-dibenzofuran-2-yl 1 CH₂CO-1-(4-acetyl)-piperazinyl4-Fluoro-dibenzofuran-2-yl 0 CH₂CO-1-(4-acetyl)-piperazinyl 934-Fluoro-dibenzofuran-2-yl 1 CH₂CO-1-(4-acetyl)-piperazinyl4-Fluoro-8-chloro-dibenzofuran- 0 CH₂CONH₂ 2-yl 944-Fluoro-8-chloro-dibenzofuran- 1 CH₂CONH₂ 2-yl Dibenzofuran-4-yl 0CH₂CONHCH₂CH₂OH 95 Dibenzofuran-4-yl 1 CH₂CONHCH₂CH₂OH Dibenzofuran-4-yl0 CH₂CONH₂ 96 Dibenzofuran-4-yl 1 CH₂CONH₂ Dibenzofuran-4-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 97 Dibenzofuran-4-yl 1CH₂CO-1-(4-acetyl)-piperazinyl Dibenzofuran-4-yl 0CH₂CO-1-(4-hydroxy)piperidinyl 98 Dibenzofuran-4-yl 1CH₂CO-1-(4-hydroxy)piperidinyl Dibenzofuran-4-yl 0CH₂CO-1-piperazinyl-N-Boc 99 Dibenzofuran-4-yl 1 CH₂CO-1-piperazinylDibenzofuran-4-yl 0 CH₂CON-(2-pyrrolidin-1-yl-ethyl) 100Dibenzofuran-4-yl 1 CH₂CON-(2-pyrrolidin-1-yl-ethyl) Dibenzofuran-4-yl 0CH₂CON-[3-(2-oxo-pyrrolidin-1-yl)-propyl] 101 Dibenzofuran-4-yl 1CH₂CON-[3-(2-oxo-pyrrolidin-1-yl)-propyl] Dibenzofuran-4-yl 0CH₂CON-(2-piperidin-1-yl-ethyl) 102 Dibenzofuran-4-yl 1CH₂CON-(2-piperidin-1-yl-ethyl) Dibenzofuran-4-yl 0CH₂CON-(2-morpholin-4-yl-ethyl) 103 Dibenzofuran-4-yl 1CH₂CON-(2-morpholin-4-yl-ethyl) Dibenzofuran-4-yl 0CH₂CO-1-(4-hydroxyethyl)-piperazinyl 104 Dibenzofuran-4-yl 1CH₂CO-1-(4-hydroxyethyl)-piperazinyl Dibenzofuran-3-yl 0CH₂CO-1-piperazinyl-N-Boc 105 Dibenzofuran-3-yl 1 CH₂CO-1-piperazinylDibenzofuran-1-yl 0 CH₂CO-1-piperazinyl-N-Boc 106 Dibenzofuran-1-yl 1CH₂CO-1-piperazinyl Dibenzofuran-3-yl 0 CH₂CO-1-(4-acetyl)-piperazinyl107 Dibenzofuran-3-yl 1 CH₂CO-1-(4-acetyl)-piperazinyl 25Dibenzothiophen-2-yl 0 CH₂CO-1-piperazinyl-N-Boc 44 Dibenzothiophen-2-yl1 CH₂CO-1-piperazinyl Dibenzothiophen-2-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 108 Dibenzothiophen-2-yl 1CH₂CO-1-(4-acetyl)-piperazinyl Dibenzothiophen-2-yl 0CH₂CO-1-(4-ethoxycarbonyl)-piperazinyl 109 Dibenzothiophen-2-yl 1CH₂CO-1-(4-ethoxycarbonyl)-piperazinyl 18 Dibenzothiophen-2-yl 0CH₂CONH₂ 39 Dibenzothiophen-2-yl 1 CH₂CONH₂ Dibenzothiophen-4-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 110 Dibenzothiophen-4-yl 1CH₂CO-1-(4-acetyl)-piperazinyl Fluoren-1-yl 0 CH₂CONHCH₂CH₂OH 111Fluoren-1-yl 1 CH₂CONHCH₂CH₂OH Fluoren-1-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 112 Fluoren-1-yl 1CH₂CO-1-(4-acetyl)-piperazinyl Fluoren-1-yl 0CH₂CO-1-(4-hydroxy)piperidinyl 113 Fluoren-1-yl 1CH₂CO-1-(4-hydroxy)piperidinyl Fluoren-1-yl 0CH₂CO-1-(4-hydroxyethyl)-piperazinyl 115 Fluoren-1-yl 1CH₂CO-1-(4-hydroxyethyl)-piperazinyl Fluoren-1-yl 0CH₂CO-1-piperazinyl-N-Boc 116 Fluoren-1-yl 1 CH₂CO-1-piperazinylFluoren-2-yl 0 CH₂CON(CH₃)₂ 118 Fluoren-2-yl 1 CH₂CON(CH₃)₂ Fluoren-2-yl0 CH₂CO—N-pyrrolidinyl 119 Fluoren-2-yl 1 CH₂CO—N-pyrrolidinylFluoren-2-yl 0 CH₂CONHCH(CH₃)₂ 120 Fluoren-2-yl 1 CH₂CONHCH(CH₃)₂Fluoren-2-yl 0 CH₂CONHCH₂CH₂OH 121 Fluoren-2-yl 1 CH₂CONHCH₂CH₂OHFluoren-2-yl 0 CH₂CO-1-(4-hydroxy)piperidinyl 122 Fluoren-2-yl 1CH₂CO-1-(4-hydroxy)piperidinyl Fluoren-2-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 123 Fluoren-2-yl 1CH₂CO-1-(4-acetyl)-piperazinyl Fluoren-4-yl 0 CH₂CON(CH₃)₂ 125Fluoren-4-yl 1 CH₂CON(CH₃)₂ Fluoren-4-yl 0 CH₂CONHCH(CH₃)₂ 126Fluoren-4-yl 1 CH₂CONHCH(CH₃)₂ Fluoren-4-yl 0 CH₂CONHCH₂CH₂OH 127Fluoren-4-yl 1 CH₂CONHCH₂CH₂OH Fluoren-4-yl 0CH₂CO-1-(4-hydroxy)piperidinyl 128 Fluoren-4-yl 1CH₂CO-1-(4-hydroxy)piperidinyl Fluoren-4-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 129 Fluoren-4-yl 1CH₂CO-1-(4-acetyl)-piperazinyl Fluoren-4-yl 0 CH₂CO-1-piperazinyl-N-Boc130 Fluoren-4-yl 1 CH₂CO-1-piperazinyl 24 Fluoren-4-yl 0CH₂CO-1-(4-hydroxyethyl)-piperazinyl 43 Fluoren-4-yl 1CH₂CO-1-(4-hydroxyethyl)-piperazinyl Fluoren-4-yl 0CH₂CO-1-(4-formyl)-piperazinyl 131 Fluoren-4-yl 1CH₂CO-1-(4-formyl)-piperazinyl 2-Phenylbenzofuran-3-yl 0 CH₂CONH₂ 1322-Phenylbenzofuran-3-yl 1 CH₂CONH₂ 2-Phenylbenzofuran-3-yl 0CH₂CO—N-pyrrolidinyl 133 2-Phenylbenzofuran-3-yl 1 CH₂CO—N-pyrrolidinyl2-Phenybenzofuran-3-yl 0 CH₂CH₂CONH₂ 134 2-Phenylbenzofuran-3-yl 1CH₂CH₂CONH₂ 2-Phenylbenzofuran-3-yl 0 CH₂CH₂CO—N-pyrrolidinyl 1352-Phenylbenzofuran-3-yl 1 CH₂CH₂CO—N-pyrrolidinyl 202-Phenylbenzofuran-3-yl 0 CH₂CON(CH₃)₂ 46 2-Phenylbenzofuran-3-yl 1CH₂CON(CH₃)₂ 2-Phenylbenzofuran-3-yl 0 CH₂CH₂CON(CH₃)₂ 1362-Phenylbenzofuran-3-yl 1 CH₂CH₂CON(CH₃)₂ 2-Phenylbenzofuran-3-yl 0CH₂CONHCH(CH₃)₂ 137 2-Phenylbenzofuran-3-yl 1 CH₂CONHCH(CH₃)₂2-Phenylbenzofuran-3-yl 0 CH₂CH₂CONHCH(CH₃)₂ 138 2-Phenylbenzofuran-3-yl1 CH₂CH₂CONHCH(CH₃)₂ 2-Phenylbenzofuran-3-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 139 2-Phenylbenzofuran-3-yl 1CH₂CO-1-(4-acetyl)-piperazinyl 2-Phenylbenzofuran-3-yl 0CH₂CH₂CO-1-(4-acetyl)-piperazinyl 140 2-Phenylbenzofuran-3-yl 1CH₂CH₂CO-1-(4-acetyl)-piperazinyl 3-Phenylbenzothiophen-2-yl 0 CH₂CONH₂141 3-Phenylbenzothiophen-2-yl 1 CH₂CONH₂ 27 3-phenylbenzothiophen-2-yl0 CH2—CO—N-pyrrolidinyl 28 3-phenylbenzothiophen-2-yl 0 CH2—CON(CH₃)₂ 293-phenylbenzothiophen-2-yl 0 CH2—CONHCH(CH₃)₂ 303-phenylbenzothiophen-2-yl 0 CH2—CO-1-(4-hydroxy)-piperidinyl 313-phenylbenzothiophen-2-yl 0 CH2—CO-1-(4-acetyl)-piperazinyl 323-phenylbenzothiophen-2-yl 0 CH2—CONH(CH₂)₂OH 473-phenylbenzothiophen-2-yl 1 CH2—CO—N-pyrrolidinyl 483-phenylbenzothiophen-2-yl 1 CH2—CON(CH₃)₂ 49 3-phenylbenzothiophen-2-yl1 CH2—CONHCH(CH₃)₂ 50 3-phenylbenzothiophen-2-yl 1CH2—CO-1-(4-hydroxy)-piperidinyl 51 3-phenylbenzothiophen-2-yl 1CH2—CO-1-(4-acetyl)-piperazinyl 52 3-phenylbenzothiophen-2-yl 1CH2—CONH(CH₂)₂OH 33 3-phenyl-1,4-benzodioxin-2-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 53 3-phenyl-1,4-benzodioxin-2-yl 1CH₂CO-1-(4-acetyl)-piperazinyl 3-phenyl-1,4-benzodioxin-2-yl 0CH₂CONHCH(CH₃)₂ 142 3-phenyl-1,4-benzodioxin-2-yl 1 CH₂CONHCH(CH₃)₂3-phenyl-1,4-benzodioxin-2-yl 0 CH₂CONH₂ 1433-phenyl-1,4-benzodioxin-2-yl 1 CH₂CONH₂ 6,7-dichloro-3-phenyl-1,4- 0CH₂CONH₂ benzodioxin-2-yl 144 6,7-dichloro-3-phenyl-1,4- 1 CH₂CONH₂benzodioxin-2-yl 6,7-dichloro-3-phenyl-1,4- 0CH₂CO-1-(4-acetyl)-piperazinyl benzodioxin-2-yl 1456,7-dichloro-3-phenyl-1,4- 1 CH₂CO-1-(4-acetyl)-piperazinylbenzodioxin-2-yl 148 3-phenyl-1H-indol-2-yl 0 CH₂CONH₂ 1493-phenyl-1H-indol-2-yl 1 CH₂CONH₂ 150 7-chlorodibenzofuran-1-yl 0CH₂CONH₂ 151 7-chlorodibenzofuran-1-yl 1 CH2CONH28-chlorodibenzofuran-1-yl 0 CH2CONH2 152 8-chlorodibenzofuran-1-yl 1CH2CONH2 7,8-dichlorodibenzofuran-1-yl 0 CH2CONH2 1537,8-dichlorodibenzofuran-1-yl 1 CH2CONH2

48. A use of a compound of formula (A):

wherein:

-   Ar is:

wherein:

-   -   U is CH₂, CR²⁵R²⁶, O, S(O)_(y), NR¹⁰, C(═O), C(═S), CHOH,        CHOR¹⁴, C═NOR¹⁴, or C═NNR¹²R¹³;    -   V and W are independently selected from a bond, CH₂, CR²⁵R²⁶, O,        S(O)_(y), NR¹⁰, C(═O), C(═S), CHOH, CHOR¹⁴, C═NOR¹⁴, or        C═NNR¹²R¹³;    -   rings A, B, and C are optionally substituted with one to three        groups selected from F, Cl, Br, I, OR²², OR²⁷, NR²³R²⁴, NHOH,        NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇        cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6        membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,        C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴,        NR²¹C(═S)R²², and S(O)_(y)R²²;    -   ring D is optionally substituted with one group selected from        C₁-C₆ alkyl, phenyl, and 5-10 membered heteroaryl; provided that        when V is a bond, and W is O, S(O)y or NR¹⁰, ring D is        substituted by a phenyl group;

-   Y is C₁-C₆ alkylene; or    -   (C₁-C₄ alkylene)_(m)-Z-(C₁-C₄ alkylene)_(n);        -   wherein said alkylene groups are optionally substituted with            one to three R²⁰ groups;

-   Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10    membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered    heterocycloalkylene; wherein said arylene, heteroarylene,    cycloalkylene, and heterocycloalkylene groups are optionally    substituted with one to three R²⁰ groups;

-   R¹ is selected from H, NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹,    OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³,    NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, NR²¹(SO₂)NR¹²R¹³, and C(═O)NR¹¹OR²²;

-   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl,    C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl and aryl    groups are optionally substituted with one to three R²⁰ groups;

-   R¹¹ at each occurrence is independently selected from H, C₁-C₆    alkyl, and C₆-C₁₀ aryl; wherein said alkyl and aryl groups are    optionally substituted with one to three R²⁰ groups;

-   R¹² and R¹³ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, C₆-C₁₀ aryl, and NR²³R²⁴, or R¹² and R¹³, together    with the nitrogen to which they are attached, form a 3-7 membered    heterocyclic ring;    -   wherein said alkyl and aryl groups and heterocyclic ring are        optionally substituted with one to three R²⁰ groups;

-   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,    C₆-C₁₀ aryl, and alkylaryl; wherein said alkyl, aryl and alkylaryl    groups are optionally substituted with one to three R²⁰ groups;

-   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,    OR²², OR²⁷, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl optionally    substituted with OH, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,    3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,    arylalkyl, ═O, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,    NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and    S(O)_(y)R²²;

-   R²¹ at each occurrence is independently selected from H and C₁-C₆    alkyl;

-   R²² at each occurrence is independently selected from H, C₁-C₆ alkyl    optionally substituted with OH, arylalkyl and C₆-C₁₀ aryl;

-   R²³ and R²⁴ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the    nitrogen to which they are attached, form a 3-7 membered    heterocyclic ring optionally substituted with ═O;

-   R²⁵ and R²⁶ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²⁵ and R²⁶, together with the    carbon to which they are attached, form a 3-7 membered heterocyclic    ring;

-   R²⁷ at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;

-   m is 0 or 1;

-   n is 0 or 1;

-   q is 0, 1, or 2;

-   y is 0, 1, or 2;    and the stereoisomeric forms, mixtures of stereoisomeric forms or    pharmaceutically acceptable salts forms thereof,    for the manufacture of a medicament useful for the treatment of a    disease or a disorder selected from the group consisting of    sleepiness associated with narcolepsy, obstructive sleep apnea or    shift work disorder; Parkinson's disease; Alzheimer's disease;    attention deficit disorder; attention deficit hyperactivity    disorder; depression; and fatigue.

49. The use of a compound of formula (A) according to claim 48 for themanufacture of a medicament useful for the treatment of sleepinessassociated with narcolepsy.

50. A use of a compound of formula (A)

wherein:

-   Ar is:

wherein:

-   -   U is CH₂, CR²⁵R²⁶, O, S(O)_(y), NR¹⁰, C(═O), C(═S), CHOH,        CHOR¹⁴, C═NOR¹⁴, or C═NNR¹²R¹³;    -   V and W are independently selected from a bond, CH₂, CR²⁵R²⁶, O,        S(O)_(y), NR¹⁰, C(═O), C(═S), CHOH, CHOR¹⁴, C═NOR¹⁴, or        C═NNR¹²R¹³;    -   rings A, B, and C are optionally substituted with one to three        groups selected from F, Cl, Br, I, OR²², OR²⁷, NR²³R²⁴, NHOH,        NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇        cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6        membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,        C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴,        NR²¹C(═S)R²², and S(O)_(y)R²²;    -   ring D is optionally substituted with one group selected from        C₁-C₆ alkyl, phenyl, and 5-10 membered heteroaryl; provided that        when V is a bond, and W is O, S(O)_(y) or NR¹⁰, ring D is        substituted by a phenyl group;

-   Y is C₁-C₆ alkylene; or    -   (C₁-C₄ alkylene)_(m)-Z-(C₁-C₄ alkylene)_(n);        -   wherein said alkylene groups are optionally substituted with            one to three R²⁰ groups;

-   Z is O, NR^(10A), S(O), CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10    membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered    heterocycloalkylene; wherein said arylene, heteroarylene,    cycloalkylene, and heterocycloalkylene groups are optionally    substituted with one to three R²⁰ groups;

-   R¹ is selected from H, NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹,    OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³,    NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, NR²¹(SO₂)NR¹²R¹³, and C(═O)NR¹¹OR²²;

-   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl,    C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl and aryl    groups are optionally substituted with one to three R²⁰ groups;

-   R¹¹ at each occurrence is independently selected from H, C₁-C₆    alkyl, and C₆-C₁₀ aryl; wherein said alkyl and aryl groups are    optionally substituted with one to three R²⁰ groups;

-   R¹² and R¹³ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, C₆-C₁₀ aryl, and NR²³R²⁴, or R¹² and R¹³, together    with the nitrogen to which they are attached, form a 3-7 membered    heterocyclic ring;    -   wherein said alkyl and aryl groups and heterocyclic ring are        optionally substituted with one to three R²⁰ groups;

-   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,    C₆-C₁₀ aryl, and alkylaryl; wherein said alkyl, aryl and alkylaryl    groups are optionally substituted with one to three R¹⁰ groups;

-   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,    OR²², OR²⁷, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl optionally    substituted with OH, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,    3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,    arylalkyl, ═O, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,    NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and    S(O)_(y)R²²;

-   R²¹ at each occurrence is independently selected from H and C₁-C₆    alkyl;

-   R²² at each occurrence is independently selected from H, C₁-C₆ alkyl    optionally substituted with OH, arylalkyl and C₆-C₁₀ aryl;

-   R²³ and R²⁴ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the    nitrogen to which they are attached, form a 3-7 membered    heterocyclic ring optionally substituted with ═O;

-   R²⁵ and R²⁶ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²⁵ and R²⁶, together with the    carbon to which they are attached, form a 3-7 membered heterocyclic    ring;

-   R²⁷ at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;

-   m is 0 or 1;

-   n is 0 or 1;

-   q is 0, 1, or 2;

-   y is 0, 1, or 2;    and the stereoisomeric forms, mixtures of stereoisomeric forms or    pharmaceutically acceptable salts forms thereof,    for the manufacture of a medicament useful for the treatment of a    sleep-affecting disease or disorder in order to promote wakefulness.

51. A use of a compound of formula (A)

wherein:

-   Ar is:

wherein:

-   -   U is CH₂, CR²⁵R²⁶, O, S(O)_(y), NR¹⁰, C(═O), C(═S), CHOH,        CHOR¹⁴, C═NOR¹⁴, or C═NNR¹²R¹³;    -   V and W are independently selected from a bond, CH₂, CR²⁵R²⁶, O,        S(O)_(y), NR¹⁰, C(═O), C(═S), CHOH, CHOR¹⁴, C═NOR¹⁴, or        C═NNR¹²R¹³;    -   rings A, B, and C are optionally substituted with one to three        groups selected from F, Cl, Br, I, OR²², OR²⁷, NR²³R²⁴, NHOH,        NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇        cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6        membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,        C(═O)NR²³R²⁴, NR²¹C(═O)R²³, NR²¹CO₂R²², OC(═O)NR²³R²⁴,        NR²¹C(═S)R²², and S(O)_(y)R²²;    -   ring D is optionally substituted with one group selected from        C₁-C₆ alkyl, phenyl, and 5-10 membered heteroaryl; provided that        when V is a bond, and W is O, S(O)_(y) or NR¹¹, ring D is        substituted by a phenyl group;

-   Y is C₁-C₆ alkylene; or    -   (C₁-C₄ alkylene)_(m)-Z-(C₁-C₄ alkylene)_(n);        -   wherein said alkylene groups are optionally substituted with            one to three R²⁰ groups;

-   Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10    membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered    heterocycloalkylene; wherein said arylene, heteroarylene,    cycloalkylene, and heterocycloalkylene groups are optionally    substituted with one to three R²⁰ groups;

-   R¹ is selected from H, NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹,    OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³,    NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, NR²¹ (SO₂)NR¹²R¹³, and    C(═O)NR¹¹OR²²;

-   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl,    C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl and aryl    groups are optionally substituted with one to three R²⁰ groups;

-   R¹¹ at each occurrence is independently selected from H, C₁-C₆    alkyl, and C₆-C₁₀ aryl; wherein said alkyl and aryl groups are    optionally substituted with one to three R²⁰ groups;

-   R¹² and R¹³ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, C₆-C₁₀ aryl, and NR²³R²⁴, or R¹² and R¹³, together    with the nitrogen to which they are attached, form a 3-7 membered    heterocyclic ring;    -   wherein said alkyl and aryl groups and heterocyclic ring are        optionally substituted with one to three R²⁰ groups;

-   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,    C₆-C₁₀ aryl, and alkylaryl; wherein said alkyl, aryl and alkylaryl    groups are optionally substituted with one to three R²⁰ groups;

-   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,    OR²², OR²⁷, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl optionally    substituted with OH, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,    3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,    arylalkyl, ═O, C(═O)R²², CO₂R²²C(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²²,    NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²;

-   R²¹ at each occurrence is independently selected from H and C₁-C₆    alkyl;

-   R²² at each occurrence is independently selected from H, C₁-C₆ alkyl    optionally substituted with OH, arylalkyl and C₆-C₁₀ aryl;

-   R²³ and R²⁴ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the    nitrogen to which they are attached, form a 3-7 membered    heterocyclic ring optionally substituted with ═O;

-   R²⁵ and R²⁶ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²⁵ and R²⁶, together with the    carbon to which they are attached, form a 3-7 membered heterocyclic    ring;

-   R²⁷ at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;

-   m is 0 or 1;

-   n is 0 or 1;

-   q is 0, 1, or 2;

-   y is 0, 1, or 2;    and the stereoisomeric forms, mixtures of stereoisomeric forms or    pharmaceutically acceptable salts forms thereof,    for the manufacture of a medicament useful for the treatment of a    neurological disease or disorder selected from Parkinson's disease;    Alzheimer's disease; attention deficit disorder; attention deficit    hyperactivity disorder; depression; and fatigue associated with a    neurological disease or disorder.

52. A pharmaceutical composition comprising a compound of formula (A):

wherein:

-   Ar is:

wherein:

-   -   U is CH₂, CR²⁵R²⁶, O, S(O)_(y), NR¹¹, C(═O), C(═S), CHOH,        CHOR¹⁴, C═NOR¹⁴, or C═NNR¹²R¹³;    -   V and W are independently selected from a bond, CH₂, CR²⁵R²⁶, O,        S(O)_(y), NR¹⁰, C(═O), C(═S), CHOH, CHOR¹⁴, C═NOR¹⁴, or        C═NNR¹²R¹³;    -   rings A, B, and C are optionally substituted with one to three        groups selected from F, Cl, Br, I, OR²², OR²⁷, NR²³R²⁴, NHOH,        NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇        cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6        membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,        C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴,        NR²¹C(═S)R²², and S(O)_(y)R²²;    -   ring D is optionally substituted with one group selected from        C₁-C₆ alkyl, phenyl, and 5-10 membered heteroaryl; provided that        when V is a bond, and W is O, S(O)_(y) or NR¹¹, ring D is        substituted by a phenyl group;

-   Y is C₁-C₆ alkylene; or    -   (C₁-C₄ alkylene)_(m)-Z-(C₁-C₄ alkylene)_(n);        -   wherein said alkylene groups are optionally substituted with            one to three R²⁰ groups;

-   Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10    membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered    heterocycloalkylene; wherein said arylene, heteroarylene,    cycloalkylene, and heterocycloalkylene groups are optionally    substituted with one to three R²⁰ groups;

-   R¹ is selected from H, NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹,    OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³,    NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, NR²¹ (SO₂)NR¹²R¹³, and    C(═O)NR¹¹OR²²;

-   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl,    C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl and aryl    groups are optionally substituted with one to three R²⁰ groups;

-   R¹¹ at each occurrence is independently selected from H, C₁-C₆    alkyl, and C₆-C₁₀ aryl; wherein said alkyl and aryl groups are    optionally substituted with one to three R²⁰ groups;

-   R¹² and R¹³ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, C₆-C₁₀ aryl, and NR²³R²⁴, or R¹² and R¹³, together    with the nitrogen to which they are attached, form a 3-7 membered    heterocyclic ring;    -   wherein said alkyl and aryl groups and heterocyclic ring are        optionally substituted with one to three R²⁰ groups;

-   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,    C₆-C₁₀ aryl, and alkylaryl; wherein said alkyl, aryl and alkylaryl    groups are optionally substituted with one to three R²⁰ groups;    -   R²⁰ at each occurrence is independently selected from F, Cl, Br,        I, OR²², OR²⁷, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl        optionally substituted with OH, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6        membered heteroaryl, arylalkyl, ═O, C(═O)R²², CO₂R²², OC(═O)R²²,        C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴,        NR²¹C(═S)R²², and S(O)_(y)R²²;

-   R²¹ at each occurrence is independently selected from H and C₁-C₆    alkyl;

-   R²² at each occurrence is independently selected from H, C₁-C₆ alkyl    optionally substituted with OH, arylalkyl and C₆-C₁₀ aryl;

-   R²³ and R²⁴ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the    nitrogen to which they are attached, form a 3-7 membered    heterocyclic ring optionally substituted with ═O;

-   R²⁵ and R²⁶ at each occurrence are each independently selected from    H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²⁵ and R²⁶, together with the    carbon to which they are attached, form a 3-7 membered heterocyclic    ring;

-   R²⁷ at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;

-   m is 0 or 1;

-   n is 0 or 1;

-   q is 0, 1, or 2;

-   y is 0, 1, or 2;    and with the exclusion of the compounds wherein:    -   U is CH₂; and    -   Y is C₁-C₆ alkylene optionally substituted with C₁-C₆ alkylene;        and    -   R¹ is CONH₂, or CO₂R¹¹ with R¹¹═H or C₁-C₆ alkyl;        and the stereoisomeric forms, mixtures of stereoisomeric forms        or pharmaceutically acceptable salts forms thereof,        in admixture with one or more pharmaceutically acceptable        excipients.

53. A method for preparing a compound of claims 1 to 47, comprising thesteps of:

-   -   a1) reacting a compound F with a compound G to form a compound        of formula (Ia):

-   -   wherein Ar, Y, R¹ are as defined in claim 1, q=0 and LG is a        leaving group; and optionally    -   b1) isolating the formed compound (Ia).

54. The method according to claim 53, wherein the compound F is formedby reacting a compound C with thiourea and a suitable acid HA:

55. A method for preparing a compound of claims 1 to 47, comprising thesteps of:

-   -   a2) reacting a compound E with a compound G to form a compound        of formula (Ia):

-   -   wherein Ar, Y, R¹ are as defined in claim 1, q=0 and LG is a        leaving group; and optionally    -   b2) isolating the formed compound (Ia).

56. The method according to claim 55, wherein the compound E is formedby reacting a compound B with the thioacetamide:

57. A method for preparing a compound of claims 1 to 47, comprising thesteps of:

-   -   a3) reacting a compound A with a compound D to form a compound        of formula (Ia):

-   -   wherein Ar, Y, R¹ are as defined in claim 1 and q=0; and        optionally    -   b3) isolating the formed compound of formula (Ia).

58. A method for preparing a compound of claims 1 to 47 comprising thesteps of:

-   -   a4) reacting a compound C with a compound H to form a compound        (Ia):

-   -   wherein Ar, Y, R¹ are as defined in claim 1 and q=0; and        optionally    -   b4) isolating the formed compound (Ia).

59. A method for preparing a compound of claims 1 to 47 comprising thesteps of:

-   -   a4) reacting a compound B with a compound H to form a compound        (Ia):

-   -   wherein Ar, Y, R¹ are as defined in claim 1 and q=0; and        optionally    -   b4) isolating the formed compound (Ia).

60. The method according to any of claims 53 to 59, further comprisingthe steps of:

-   -   a5) reacting the compound (Ia) with an appropriate oxidizing        agent fo form a compound (Ib):

-   -   wherein Ar, Y, R¹ are as defined in claim 1 and q is 1 or 2; and        optionally    -   b5) isolating the formed compound (Ib).

Although the present invention has been described in considerabledetail, those skilled in the art will appreciate that numerous changesand modifications may be made to the embodiments and preferredembodiments of the invention and that such changes and modifications maybe made without departing from the spirit of the invention. It istherefore intended that the appended claims cover all equivalentvariations as fall within the scope of the invention.

1. A compound of formula (A):

wherein Ar is:

wherein: V is CH₂, CR²⁵R²⁶, O, S(O)_(y), NR¹⁰, C(═O), C(═S), CHOH,CHOR¹⁴, C═NOR¹⁴, or C═NNR¹²R¹³; W is selected from a bond, CH₂, CR²⁵R²⁶,O, S(O)_(y), NR¹⁰, C(═O), C(═S), CHOH, CHOR¹⁴, C═NOR¹⁴, or C═NNR¹²R¹³;ring C is optionally substituted with one to three groups selected fromF, Cl, Br, I, OR²², OR²⁷, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 memberedheterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl,C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²²,OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²; ring D is optionallysubstituted with one group selected from C₁-C₆ alkyl, phenyl, and 5-10membered heteroaryl; provided that when V is a bond, and W is O, S(O)yor NR¹⁰, ring D is substituted by a phenyl group; Y is C₁-C₆ alkylene;wherein said alkylene groups are optionally substituted with one tothree R²⁰ groups; R¹ is selected from H, NR¹²R¹³, NR²¹C(═O)R¹⁴,C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³,OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, NR²¹C(═O)NR²R¹²R¹³, NR²¹S(O)₂NR¹²R¹³, andC(═O)NR¹¹OR²²; R¹⁰ is each independently selected from H, C₁-C₆ alkyl,C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl and arylgroups are optionally substituted with one to three R²⁰ groups; R¹¹ ateach occurrence is independently selected from H, C₁-C₆ alkyl, andC₆-C₁₀ aryl; wherein said alkyl and aryl groups are optionallysubstituted with one to three R²⁰ groups; R¹² and R¹³ at each occurrenceare each independently selected from H, C₁-C₆ alkyl, C₆-C₁₀ aryl, andNR²³R²⁴, or R¹² and R¹³, together with the nitrogen to which they areattached, form a 3-7 membered heterocyclic ring; wherein said alkyl andaryl groups and heterocyclic ring are optionally substituted with one tothree R²⁰ groups; R¹⁴ at each occurrence is independently selected fromC₁-C₆ alkyl, C₆-C₁₀ aryl, and alkylaryl; wherein said alkyl, aryl andalkylaryl groups are optionally substituted with one to three R²⁰groups; R²⁰ at each occurrence is independently selected from F, Cl, Br,I, OR²², OR²⁷, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl optionallysubstituted with OH, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl,arylalkyl, ═O, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²²,NR²¹C(═O)OR²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²; R²¹ at eachoccurrence is independently selected from H and C₁-C₆ alkyl; R²² at eachoccurrence is independently selected from H, C₁-C₆ alkyl optionallysubstituted with OH, arylalkyl and C₆-C₁₀ aryl; R²³ and R²⁴ at eachoccurrence are each independently selected from H, C₁-C₆ alkyl, andC₆-C₁₀ aryl, or R²³ and R²⁴, together with the nitrogen to which theyare attached, form a 3-7 membered heterocyclic ring optionallysubstituted with ═O; R²⁵ and R²⁶ at each occurrence are eachindependently selected from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²⁵ andR²⁶, together with the carbon to which they are attached, form a 3-7membered heterocyclic ring; R²⁷ at each occurrence is independently theresidue of an amino acid after the hydroxyl group of the carboxyl groupis removed; q is 0, 1, or 2; y is 0, 1, or 2; with the exclusion of thecompounds: 3-[(methylthio)methyl]-2-phenyl-1H-inden-1-one3-[(methylsulfinyl)methyl]-2-phenyl-1H-inden-1-one and thestereoisomeric forms, mixtures of stereoisomeric forms orpharmaceutically acceptable salts forms thereof.
 2. The compoundaccording to claim 1, wherein q is 1, and the stereoisomeric forms,mixtures of stereoisomeric forms or pharmaceutically acceptable saltsforms thereof.
 3. The compound according to claim 1, wherein R¹ is H,and the stereoisomeric forms, mixtures of stereoisomeric forms orpharmaceutically acceptable salts forms thereof.
 4. The compoundaccording to claim 1, wherein R¹ is selected from NR¹²R¹³, NR²¹C(═O)R¹⁴;C(═O)NR¹²R¹³; C(═NR¹¹)NR¹²R¹³, NR²¹C(═O)NR¹²R¹³, and the stereoisomericforms, mixtures of stereoisomeric forms or pharmaceutically acceptablesalts forms thereof.
 5. The compound according to claim 4, wherein R¹ isselected from NR¹²R¹³, NR²¹C(═O)R¹⁴; C(═O)NR¹²R¹³; C(═NR¹¹)NR¹²R¹³,NR²¹C(═O)NR¹²R¹³, and the stereoisomeric forms, mixtures ofstereoisomeric forms or pharmaceutically acceptable salts forms thereof.6. The compound according to claim 5, wherein R¹ is C(═O)NR¹²R¹³, andthe stereoisomeric forms, mixtures of stereoisomeric forms orpharmaceutically acceptable salts forms thereof.
 7. The compoundaccording to claim 1, wherein R¹² and R¹³ are each independentlyselected from H, C₁-C₆ alkyl and NR²³R²⁴, and the stereoisomeric forms,mixtures of stereoisomeric forms or pharmaceutically acceptable saltsforms thereof.
 8. The compound according to claim 6, wherein R¹² and R¹³together with the nitrogen to which they are attached, form a 3-7membered heterocyclic ring, wherein said heterocyclic ring is optionallysubstituted with one R²⁰ group, and the stereoisomeric forms, mixturesof stereoisomeric forms or pharmaceutically acceptable salts formsthereof.
 9. The compound according to claim 8, wherein said heterocyclicring is unsubstituted, and the stereoisomeric forms, mixtures ofstereoisomeric forms or pharmaceutically acceptable salts forms thereof.10. The compound according to claim 4, wherein R¹ is selected fromC(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹,and NR²¹S(O)₂NR¹²R¹³, and the stereoisomeric forms, mixtures ofstereoisomeric forms or pharmaceutically acceptable salts forms thereof.11. The compound according to claim 1, wherein V is O, S(O)_(y) or NR¹⁰,W is a bond and ring D is substituted with a phenyl, and thestereoisomeric forms, mixtures of stereoisomeric forms orpharmaceutically acceptable salts forms thereof.
 12. The compoundaccording to claim 1, wherein V is O, W is O and ring D is substitutedwith a phenyl, and the stereoisomeric forms, mixtures of stereoisomericforms or pharmaceutically acceptable salts forms thereof.
 13. Thecompound according to claim 1, wherein Y is CH₂, and the stereoisomericforms, mixtures of stereoisomeric forms or pharmaceutically acceptablesalts forms thereof.
 14. The compound according to claim 1, wherein V isO, S(O)_(y), or NR¹⁰; W is selected from a bond, O, S(O)_(y), or NR¹⁰;ring C is optionally substituted with one to three groups selected fromF, Cl, Br, I, OR²², OR²⁷, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkylphenyl, arylalkyl, and C(═O)R²²; ring D is optionally substituted withone group selected from C₁-C₆ alkyl, and phenyl; R¹ is selected fromNR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³,C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³,NR²¹S(O)₂NR¹²R¹³, and C(═O)NR¹¹OR²²; R¹⁰ is each independently selectedfrom H, C₁-C₆ alkyl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl groupis optionally substituted with one to three R²⁰ groups; R¹¹ at eachoccurrence is independently selected from H, and C₁-C₆ alkyl; whereinsaid alkyl group is optionally substituted with one to three R²⁰ groups;R¹² and R¹³ at each occurrence are each independently selected from H,and C₁-C₆ alkyl, and NR²³R²⁴, or R¹² and R¹³, together with the nitrogento which they are attached, form a 3-7 membered heterocyclic ring;wherein said alkyl group and heterocyclic ring are optionallysubstituted with one to three R²⁰ groups; R¹⁴ at each occurrence isindependently selected from C₁-C₆ alkyl and C₆-C₁₀ aryl; wherein saidalkyl, aryl and alkylaryl groups are optionally substituted with one tothree R²⁰ groups; R²⁰ at each occurrence is independently selected fromF, Cl, Br, I, OR²², OR²⁷, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyloptionally substituted with OH, phenyl, ═O, C(═O)R²², CO₂R²², OC(═O)R²²,C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹OC(═S)R²²,and S(O)_(y)R²²; R²¹ at each occurrence is independently selected from Hand C₁-C₆ alkyl; R²² at each occurrence is independently selected fromH, C₁-C₆ alkyl optionally substituted with OH, phenyl, and benzyl R²³and R²⁴ at each occurrence are each independently selected from H, C₁-C₆alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the nitrogen towhich they are attached, form a 3-7 membered heterocyclic ringoptionally substituted with ═O; R²⁷ at each occurrence is independentlythe residue of an amino acid after the hydroxyl group of the carboxylgroup is removed; q is 0, 1, or 2; y is 0, 1, or 2; and thestereoisomeric forms, mixtures of stereoisomeric forms orpharmaceutically acceptable salts forms thereof.
 15. The compoundaccording to claim 14, wherein R¹ is selected from NR²¹C(═O)R¹¹,C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, and C(═O)NR¹¹OR²², and thestereoisomeric forms, mixtures of stereoisomeric forms orpharmaceutically acceptable salts forms thereof.
 16. The compoundaccording to claim 15, wherein R¹ is C(═O)NR¹²R¹³, and thestereoisomeric forms, mixtures of stereoisomeric forms orpharmaceutically acceptable salts forms thereof.
 17. The compoundaccording to claim 16, having the structure of formula (IV)

and the stereoisomeric forms, mixtures of stereoisomeric forms orpharmaceutically acceptable salts forms thereof.
 18. The compoundaccording to claim 17, wherein V is O, S(O)_(y), or NR¹¹, W is a bondand ring D is substituted with a phenyl, and the stereoisomeric forms,mixtures of stereoisomeric forms or pharmaceutically acceptable saltsforms thereof.
 19. The compound according to claim 18, wherein V is O,or S(O)_(y), W is a bond and ring D is substituted with a phenyl, andthe stereoisomeric forms, mixtures of stereoisomeric forms orpharmaceutically acceptable salts forms thereof.
 20. The compoundaccording to claim 17, wherein V is O, W is O and ring D is substitutedwith a phenyl, and the stereoisomeric forms, mixutes of stereoisomericforms or pharmaceutically acceptable salts forms thereof.
 21. Thecompound according to claim 17, wherein Y is CH₂ or CH₂—CH₂, and thestereoisomeric forms, mixtures of stereoisomeric forms orpharmaceutically acceptable salts forms thereof.
 22. The compoundaccording to claim 1, selected in accordance with the following table:

wherein Ar, q, Y—R¹ are defined in the table below; Ring Ar q Y—R¹2-Phenylbenzofuran-3-yl 0 CH₂CONH₂ 132 2-Phenylbenzofuran-3-yl 1CH₂CONH₂ 2-Phenylbenzofuran-3-yl 0 CH₂CO—N-pyrrolidinyl 1332-Phenylbenzofuran-3-yl 1 CH₂CO—N-pyrrolidinyl 2-Phenybenzofuran-3-yl 0CH₂CH₂CONH₂ 134 2-Phenylbenzofuran-3-yl 1 CH₂CH₂CONH₂2-Phenylbenzofuran-3-yl 0 CH₂CH₂CO—N-pyrrolidinyl 1352-Phenylbenzofuran-3-yl 1 CH₂CH₂CO—N-pyrrolidinyl 202-Phenylbenzofuran-3-yl 0 CH₂CON(CH₃)₂ 46 2-Phenylbenzofuran-3-yl 1CH₂CON(CH₃)₂ 2-Phenylbenzofuran-3-yl 0 CH₂CH₂CON(CH₃)₂ 1362-Phenylbenzofuran-3-yl 1 CH₂CH₂CON(CH₃)₂ 2-Phenylbenzofuran-3-yl 0CH₂CONHCH(CH₃)₂ 137 2-Phenylbenzofuran-3-yl 1 CH₂CONHCH(CH₃)₂2-Phenylbenzofuran-3-yl 0 CH₂CH₂CONHCH(CH₃)₂ 138 2-Phenylbenzofuran-3-yl1 CH₂CH₂CONHCH(CH₃)₂ 2-Phenylbenzofuran-3-yl 0CH₂CO-1-(4-acetyl)-piperazinyl 139 2-Phenylbenzofuran-3-yl 1CH₂CO-1-(4-acetyl)-piperazinyl 2-Phenylbenzofuran-3-yl 0CH₂CH₂CO-1-(4-acetyl)- piperazinyl 140 2-Phenylbenzofuran-3-yl 1CH₂CH₂CO-1-(4-acetyl)- piperazinyl 3-Phenylbenzothiophen-2- 0 CH₂CONH₂yl 141 3-Phenylbenzothiophen-2- 1 CH₂CONH₂ yl 273-phenylbenzothiophen-2-yl 0 CH2—CO—N-pyrrolidinyl 283-phenylbenzothiophen-2-yl 0 CH2—CON(CH₃)₂ 29 3-phenylbenzothiophen-2-yl0 CH2—CONHCH(CH₃)₂ 30 3-phenylbenzothiophen-2-yl 0 CH2—CO-1-(4-hydroxy)-piperidinyl 31 3-phenylbenzothiophen-2-yl 0 CH2—CO-1-(4-acetyl)-piperazinyl 32 3-phenylbenzothiophen-2-yl 0 CH2—CONH(CH₂)₂OH 473-phenylbenzothiophen-2-yl 1 CH2—CO—N-pyrrolidinyl 483-phenylbenzothiophen-2-yl 1 CH2—CON(CH₃)₂ 49 3-phenylbenzothiophen-2-yl1 CH2—CONHCH(CH₃)₂ 50 3-phenylbenzothiophen-2-yl 1 CH2—CO-1-(4-hydroxy)-piperidinyl 51 3-phenylbenzothiophen-2-yl 1 CH2—CO-1-(4-acetyl)-piperazinyl 52 3-phenylbenzothiophen-2-yl 1 CH2—CONH(CH₂)₂OH 333-phenyl-1,4-benzodioxin- 0 CH₂CO-1-(4-acetyl)-piperazinyl 2-yl 533-phenyl-1,4-benzodioxin- 1 CH₂CO-1-(4-acetyl)-piperazinyl 2-yl3-phenyl-1,4-benzodioxin- 0 CH₂CONHCH(CH₃)₂ 2-yl 1423-phenyl-1,4-benzodioxin- 1 CH₂CONHCH(CH₃)₂ 2-yl3-phenyl-1,4-benzodioxin- 0 CH₂CONH₂ 2-yl 143 3-phenyl-1,4-benzodioxin-1 CH₂CONH₂ 2-yl 6,7-dichloro-3-phenyl-1,4- 0 CH₂CONH₂ benzodioxin-2-yl144 6,7-dichloro-3-phenyl-1,4- 1 CH₂CONH₂ benzodioxin-2-yl6,7-dichloro-3-phenyl-1,4- 0 CH₂CO-1-(4-acetyl)-piperazinylbenzodioxin-2-yl 145 6,7-dichloro-3-phenyl-1,4- 1CH₂CO-1-(4-acetyl)-piperazinyl benzodioxin-2-yl 1483-phenyl-1H-indol-2-yl 0 CH₂CONH₂ 149 3-phenyl-1H-indol-2-yl 1 CH₂CONH₂

and the stereoisomeric forms, mixtures of stereoisomeric forms orpharmaceutically acceptable salts forms thereof.
 23. A pharmaceuticalcomposition comprising a compound of claim 1, or the stereoisomericforms, mixtures of stereoisomeric forms or pharmaceutically acceptablesalts forms thereof, in admixture with one or more pharmaceuticallyacceptable excipients.
 24. A method for preparing a compound of claim 1and the stereoisomeric forms, mixtures of stereoisomeric forms orpharmaceutically acceptable salts forms thereof, comprising the stepsof: a1) reacting a compound F with a compound G to form a compound offormula (Ia):

wherein Ar, Y, R¹ are as defined in claim 1, q=0 and LG is a leavinggroup; and optionally b1) isolating the formed compound (Ia).
 25. Themethod according to claim 24, wherein the compound F is formed byreacting a compound C with thiourea and a suitable acid HA:


26. A method for preparing a compound of claim 1 and the stereoisomericforms, mixtures of stereoisomeric forms or pharmaceutically acceptablesalts forms thereof, comprising the steps of: a2) reacting a compound Ewith a compound G to form a compound of formula (Ia):

wherein Ar, Y, R¹ are as defined in claim 1, q=0 and LG is a leavinggroup; and optionally b2) isolating the formed compound (Ia).
 27. Themethod according to claim 26, wherein the compound E is formed byreacting a compound B with the thioacetamide:


28. A method for preparing a compound of claim 1 and the stereoisomericforms, mixtures of stereoisomeric forms or pharmaceutically acceptablesalts forms thereof, comprising the steps of: a3) reacting a compound Awith a compound D to form a compound of formula (Ia):

wherein Ar, Y, R¹ are as defined in claim 1 and q=0; and optionally b3)isolating the formed compound of formula (Ia).
 29. A method forpreparing a compound of claim 1 and the stereoisomeric forms, mixturesof stereoisomeric forms or pharmaceutically acceptable salts formsthereof, comprising the steps of: a4) reacting a compound C with acompound H to form a compound (Ia):

wherein Ar, Y, R¹ are as defined in claim 1 and q=0; and optionally b4)isolating the formed compound (Ia).
 30. A method for preparing acompound of claim 1 and the stereoisomeric forms, mixtures ofstereoisomeric forms or pharmaceutically acceptable salts forms thereof,comprising the steps of: a4) reacting a compound B with a compound H toform a compound (Ia):

wherein Ar, Y, R¹ are as defined in claim 1 and q=0; and optionally b4)isolating the formed compound (Ia).
 31. The method according to any oneof claims 24, 26, 28, 29, or 30, further comprising the steps of: a5)reacting the compound (Ia) with an appropriate oxidizing agent to form acompound (Ib):

wherein Ar, Y, R¹ are as defined in claim 1 and q is 1 or 2; andoptionally b5) isolating the formed compound (Ib).